🎙️ Episode 82: JAK2 Inhibition Drives RAS Pathway Mutant Clonal Selection in Myeloproliferative Neoplasms
🧬 In this episode of PaperCast Base by Base, we explore how JAK2 inhibition by ruxolitinib reshapes clonal dynamics in myelofibrosis by mediating the expansion of RAS pathway-mutated clones in myeloproliferative neoplasms.
🔍 Study Highlights:
We conducted a longitudinal molecular analysis of myelofibrosis patients treated with ruxolitinib and observed a marked accumulation of RAS pathway mutations following JAK2 inhibitor exposure. Single-cell DNA sequencing and ex vivo treatment of patient-derived CD34+ cells demonstrated that ruxolitinib selectively enriches RAS-mutant clones even in the absence of JAK/STAT hyperactivation. Competitive co-culture and in vivo models revealed that RAS-mutated cells exhibit increased fitness and clonogenic potential under JAK2 inhibition. Mechanistic studies showed that JAK2 downregulation leads to MAPK pathway activation, which underlies the enhanced oncogenic potential of RAS-mutant clones.
🧠 Conclusion:
These insights highlight the need for pre-treatment screening of RAS mutations and support the development of combination strategies targeting both JAK/STAT and MAPK pathways to prevent clonal resistance.
🔑 SEO Keywords: genomics, what is genomics, graduate studies in genomics, functional genomics, structural genomics, genomics and proteomics
🔗 Episode Slug: jak2-inhibition-drives-ras-pathway-mutant-clonal-selection
📖 Reference:
Maslah N, Kaci N, Roux B, et al. JAK2 inhibition mediates clonal selection of RAS pathway mutations in myeloproliferative neoplasms. Nat Commun. 2025;16:6270. doi:10.1038/s41467-025-60884-1
📜 License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/
On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
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Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
(00:14):
Welcome to Base by Base, the paper cast that brings genomics
to you wherever you are. OK, so think about this for a
second. What if the very treatment, you
know, the one designed to fight cancer?
What if it actually helps other,maybe even more dangerous cells
survive? That's a provocative thought.
Right. Like, imagine a therapy.
(00:35):
It makes a patient feel better. Symptoms improve, definitely.
But underneath, it's silently letting a more aggressive
version of the disease maybe take hold.
It sounds, well, kind of paradoxical.
It does, but it's not just hypothetical.
We're talking about cancers, incredible almost scary ability
to adapt so that this constant chess game, you know, between
(00:56):
our treatments and the cancer evolving resistance and
sometimes the drug that helps can also well act as this
selective pressure, empowering new, maybe tougher mutations.
Exactly selecting for the fittest, even if fittest means
more dangerous for the patient. So today we're diving into a
really fascinating and, yeah, somewhat counterintuitive
discovery in the world of blood cancers.
(01:17):
It throws this whole idea of adaptive resistance into sharp
relief. It really does.
How could targeting one specificpathway lead to the the
outgrowth of another, potentially making the disease
even more aggressive? Stick around, you're about to
find out. This deep dive today is possible
thanks to some really groundbreaking work by a
collaborative team, mostly researchers from University of
(01:40):
Paris. Cite a PHP opera Saint Louis and
INSERM in France. Right, a strong French core.
But also with significant contributions from teams in the
US, Dana Farber Cancer Instituteand Boston Children's Hospital.
So a real international effort. Absolutely.
And you know, we should mention some key contributors like Nabi
Masla, Nina Kasi, Blondin Rue and the PI's overseeing it, Jean
(02:03):
Jacques Kalajian, Bruno Kasanat and Lena Benijiba.
Their work has really pushed forward our understanding of how
cancer clones, these different cell populations evolve under
targeted therapy pressure. Especially in myeloproliferative
neoplasms, right? Exactly MPN's.
That's the specific focus here. OK, let's set the stage a bit.
Proliferative neoplasms. MPN's.
What are these exactly? So MPN's are a group of chronic
(02:25):
blood cancers. Basically the bone marrow goes
into OverDrive and produces too many blood cells, red cells,
white cells, platelets, depending on the specific type.
And they're considered pre leukemic.
That's right. They have this potential,
unfortunately, to transform intomore aggressive diseases like
acute myeloid leukemia, AML, which is obviously much more
(02:46):
dangerous. And what drives these MPN's at
the molecular level? A lot of them are driven by
activating mutations in a key signaling pathway called the
JAXA debt pathway. Think of it like a communication
network inside the cell that tells it to grow and divide OK
and specific genes in that pathway like JK2C ALRMPL often
(03:06):
have mutations that basically get stuck in the on position.
So if the problem is an overactive JAXA debt pathway,
well, targeting it seems logical.
Which brings us to Jack's inhibitors like Ruxilotenib.
These came out about what, over a decade?
Ago, yeah, around that, that time and they really did change
the treatment landscape for MPN now.
So what was the immediate impact?
Well, Rexel Litanib for example,it's a JAK 12 inhibitor.
(03:29):
It was and still is fantastic atimproving quality of life.
It dramatically reduces symptoms, things like severe
fatigue, fevers, night sweats, and it shrinks those enlarged
spleens, which can be really uncomfortable for patients.
So definite symptomatic relief. Huge symptomatic relief.
But the question lingered about its long term impact.
(03:51):
Does it actually change the underlying disease?
Does it really improve overall survival across the board?
That's been more debated. Right.
So we have drugs that work well for symptoms.
But researchers suspected there might be more going on under the
hood, genetically speaking, especially with long term
treatment. Exactly.
The worry was, OK, we're hittingthe main driver of the JK
mutation, but is that pressure inadvertently helping other
(04:14):
cancer cells? Different clones with different
mutations? Are we accidentally changing the
genetic landscape in ways we didn't initially predict?
Like wedding one type of weed only to have another, maybe
worse one take over the garden. That's a pretty good analogy,
yeah. So how did this research team
tackle this complex question? What was their approach?
They use a really smart, multi pronged approach.
(04:36):
They didn't just rely on one type of evidence, they started
by looking at real world patientdata.
Okay, tell us about that cohort.They studied 143 patients with
myelofibrosis, which is the typeof MPN often associated with
scarring in the bone marrow, andcrucially, they split this
group. 72 patients had received rexultinib and 71 had not.
(04:57):
A treated group and a control group, essentially.
Right. And they didn't just look at one
point in time, they performed longitudinal molecular
evaluations. They used next generation
sequencing NGS to track the genetic changes in the cancer
cells over time for each patient.
So they could see how the mutation profile evolved.
Precisely. But here's where they went a
step further, and this is reallycool.
(05:18):
They use single cell DNA sequencing on actual patient
cells. Single cell.
Wow. Yeah.
This lets you see not just what mutations are present in the
whole tumor sample, but which specific mutations are in which
individual cells. It lets you map out the clonal
architecture of the different families of cancer cells and see
how those families grow or shrink over time with treatment.
That gives you incredible resolution, so you can see if,
(05:41):
say, a tiny population of cells with a certain mutation suddenly
starts expanding. Exactly.
It moves beyond just averages, but observation is one thing.
To understand the how the mechanism they needed
experiments. Right, you need to test
causality. What did they do in the lab?
They did a lot of in vitro work experiments and lab dishes using
established cancer cell lines like Hel and Yuki one which have
(06:03):
Jake mutations and also importantly patient derived
cells. And in vivo too.
Yes, also in vivo using mouse models.
This combination is powerful because you can control the
conditions very precisely in thelab and then see if the same
effects hold up in a living Organism.
What were they simulating in these experiments?
They ran pompetition assays. Basically they'd mix cells with,
(06:23):
say, Ras mutation together with cells that didn't have it, or
cells with just the original JAK2 mutation, and then expose them
to rexolodib. To see who wins out under drug
pressure. Exactly.
See which population thrives when JK signaling is blocked.
They even specifically knocked down the Jack 2 gene in some
experiments to really isolate the effect of inhibiting that
(06:44):
specific target. Very thorough.
And one more thing, they validated their findings using
large public data sets like the BEAT AML cohort.
This helps ensure their results aren't just specific to their
patient group, but might reflectA broader biological principle.
It adds a lot of confidence. OK, so really comprehensive
strategy, patient data, single cell analysis, lab experiments,
(07:05):
mouse models, large data set validation.
So what did all this uncover? What's the big finding about
Ruxilet and NIB? The headline finding is a really
strong and frankly concerning link between Ruxilet and NIB
treatment and the rise of mutations in the Ras pathway.
Res like NRS Krayeus, right? Those well known cancer genes.
Exactly. Those, yeah, Nres, Krayefs also
(07:27):
CBL, which is part of that pathway regulation.
They found that in the patients treated with Ruxilet and NIB,
there was a significant accumulation A clonal outgrowth
of cells carrying these Ras pathway mutations.
How significant? Get this in the ruxolidin of
treated patients, 28% of all thenew mutations they detected over
time were in the Ras pathway. Compare that to only 7% in the
(07:49):
untreated patients. Wow, OK, that's a four fold
difference. That's not subtle.
Not subtle at all. And it wasn't just about new
mutations appearing. They looked at the variant
allele frequency, basically whatpercentage of the cancer cells
carried an existing RES mutation.
Right. How dominant that clone was.
Exactly, and the VAF of these RES mutations significantly
increased only in the group getting rexilitinib.
(08:11):
This really points towards the drug actively selecting for
these RES mutated cells. And was this effect specific to
RES or did other mutations also increase?
It seemed pretty specific to theRas pathway.
They looked at other common mutations found in MPNS, like AS
XL1, and didn't see the same pattern of outgrowth
specifically linked to ruxilitinib treatment.
(08:32):
OK. So the drug seems to favor RES
mutated cells, Yeah. But the critical question is
what does that mean for the patients?
Does it affect their outcome? And that's where the findings
become really stark. Yes, it dramatically affected
patient prognosis, but here's the key twist Only when patients
were on rexilitinib. Only in the treated group.
Only in the treated group, if you had ARAS mutation and were
(08:55):
taking rexilitinib, your prognosis was significantly
worse, your overall survival waslower and your transformation
free survival was lower. Let's break that down.
Overall survival. Median overall survival for
rexilitinib patients with RES mutation was about 7.6 years.
For those on rexilinib without RES mutation, it was over 18.5
(09:15):
years. That's a.
Huge difference, more than double the survival time if you
didn't have that res mutation while on the drug.
A massive difference and transformation free survival.
Can you explain that one? Sure, that's the time until the
disease progresses into a more aggressive form, usually acute
myeloid leukemia, AML or milder spilastic syndrome.
MD's and the. Impact.
(09:35):
There was, if anything even moredramatic.
In the rexilutinib group, if youhad a RES mutation, you had a
47% chance of transforming to AML or MD's.
Nearly half. Nearly half.
But if you had a RES mutation and were not on rexilutinib,
your chance of transformation was only 17%.
OK. So the combination of the drug
in the RES mutation is particularly bad news for
(09:58):
disease progression. It strongly suggests the drug is
creating an environment where these res mutated clones don't
just survive, they actively thrive and drive the disease
towards a more aggressive state.Which is deeply concerning So
the drug creates the pressure, but how?
What's the actual mechanism? How does inhibiting Jake help
Ras? That's.
What their lab experiments helped figure out.
(10:20):
The ex vivo and in vivo work showed directly that rexilutinib
selects for these RES mutated clones.
These cells showed increased fitness.
They grew better, proliferated more, even when Jack stat
signaling was shut down by the drug.
So they didn't need the Jake pathway anymore.
It seems they became less reliant on it or found
workarounds, and the key workaround involved another
major signaling pathway, the MAPK pathway.
(10:42):
Which is often downstream of Ras.
Right. Yeah, exactly.
Ras activation typically triggers the MPK pathway, which
also drives cell growth and survival.
The researchers found that this resistance to rexilit NIB in RES
mutated cells depended on MEPK activation.
How do they? Show that.
Crucially, when they experimentally inhibited the MPK
pathway using MEK inhibitors, for example, the Rs mutated
(11:05):
cells suddenly became sensitive to rexilit NIB again.
Ah OK, so blocking Jake selects for res mutants.
These mutants rely on MAP PK, and if you block MBK 2, you
restore sensitivity to the J inhibitor that connects the
dots. It really does.
It shows that the MBK pathway isessential for these Ras clones
to thrive under ruxilitinib pressure.
(11:26):
But then there was another twist.
Wasn't there something about an inverse relationship with JK2
itself? Yes, this was perhaps the most
counterintuitive part. They found that activating the
Rasmat K pathway, for instance by overexpressing Nras, actually
led to decreased levels of JK2 mRNA and protein.
Wait, so turning on the Ras pathway turned down the JK
pathway component? Kind of looks that way.
And they saw hints of this in the patient data too.
(11:48):
Patients whose cancers had low JK2 expression tended to have
stronger signs of rasmakay pathway activity and more active
cell division. So what's the thinking behind
that? Why would that happen?
The hypothesis is fascinating. It involves something called
oncogene induced senescence or stress.
Basically, if a cancer gene likeRES becomes too active, it can
(12:09):
trigger cellular alarm bells that force the cell to stop,
dividing, or even self destruct.It's a built in safety
mechanism. The idea is that maybe the
baseline activity from the mutated JAK 2, even if it's
driving the cancer initially, might also contribute just
enough pathway activity to keep this oncogene induced stress
response partially active in cells that also have ARAS
(12:30):
mutation. It's like having two
accelerators push part way down is actually worse for the cell
than just one push down hard. So the Jak 2 activity is almost
protective in a weird way against the Ras mutation going
completely wild. Potentially yes.
So when you treat with ruxilitinib, you inhibit JAK,
you take away that break or thatsource of stress and that might
be what fully unleashes the proliferative potential of the
(12:53):
pre-existing RES mutation. The Ras mutation was already
there, maybe in a small clone, but it couldn't fully take off
until JAK 2 was inhibited. Wow, so inhibiting 1 oncogenic
pathway removes a restraint on another that is complex?
Deeply complex, it highlights just how interconnected these
signaling networks are and how cancer can exploit these
(13:14):
connections in unexpected ways. This.
Is truly a deep dive into cancers adaptability?
What are the big takeaways here for patients?
For researchers. I think the main take away is
that JAK 2 inhibition, while clearly beneficial for symptoms
in MPN's, isn't a free lunch. Molecular speaking.
It can create this specific selective pressure that favors
the outgrowth of res mutated clones.
(13:35):
And these clones are bad news. And these clones are associated
with worse outcomes, specifically disease
transformation and lower survival when under Jack
inhibition. It reveals the sort of
paranoxical mechanism where inhibiting 1 pathway allows
another oncogenic pathway which might have been suppressed or
held in check to really flourish.
(13:57):
You mentioned a Goldilocks principle earlier.
Yeah, it's almost like that. Maybe too much signaling through
both jackstat and rasmapic pathways triggers cell
senescence or death. But if you inhibit Jackstat, you
might bring the rasmapic signaling into a just right zone
where it can drive aggressive proliferation without tripping
those safety alarms. This feels like it has immediate
(14:17):
clinical relevance. It's not just interesting
biology. Absolutely.
It strongly argues for screeningMPN patients for pre-existing
Ras mutations before starting them on a Jack inhibitor like
rexaltinib. Forewarned is forearmed.
Exactly, and it also suggests that regular molecular
monitoring during treatment is crucial.
We need to watch out for these Ras clones emerging or
(14:37):
expanding. And if they do emerge, what
then? Well, that's the next challenge,
but this research points towardsrational combination strategies.
If the resistance depends on theMEPK pathway, maybe combining
the Jake inhibitor with MEK inhibitor which targets METK
could prevent or overcome this resistance.
And you said trials for that arealready happening.
(14:59):
Yes, clinical trials exploring Jplus MEK inhibition are
underway. This kind of preclinical
mechanistic work directly informs those next generation
trial designs. Does this principle inhibiting 1
pathway unleashing another potentially apply beyond MPNS?
The authors certainly suggest itmight.
Cancers where Ras pathway mutations are common, think
(15:20):
pancreatic cancer. Some lung cancers, Melanoma
could potentially exhibit similar dynamics if treated with
drugs that affect related pathways.
Could it explain some mixed results with Jake inhibitors and
solid tumors perhaps? It's possible, or even the
observation, that ruxilithinib has sometimes been linked to an
increased risk of certain aggressive skin cancers, which
often carry RES mutations. It underscores this major
(15:42):
challenge in cancer therapy. Cancer is an adaptive system.
You push it here, it bulges out there.
But we need to be really clear here.
Despite this finding, JAK inhibitors are still valuable
tools for MPN patients, aren't they?
Oh, absolutely. Crucial to emphasize that yes,
JK inhibitors like roxalitinib remain a cornerstone of therapy
(16:03):
for many MPN patients. They provide significant symptom
relief and may offer survival benefits for certain patient
groups. So this isn't about throwing the
baby out with the bathwater. Not at all.
It's about refining our approach.
It's about understanding the risks, identifying patients who
might be susceptible to this resistance mechanism, and
developing smarter strategies, maybe combinations, maybe closer
(16:25):
monitoring to maximize the benefit while minimizing the
potential downsides. It's about personalization.
And like all studies, this one had limitations that point
towards as future research directions.
Sure. As we mentioned, the patient
cohort analysis was retrospective, looking back at
records, which always carries potential biases.
For example, patients who got rexiletinib might have already
(16:47):
had more aggressive disease. Prospective studies are needed
to confirm these findings definitively.
Right, following patients forward in time.
Exactly. Also, the number of RES mutated
patients in the non rexiletinib group was relatively small,
which limits the statistical power for some comparisons.
And while their lab data hinted the selection might happen
regardless of the initial MPN driver mutation, J AK2C ALRMPLA
(17:11):
lot of the deep mechanistic workfocused on the JAK 2V-617-F
context. More research on how this plays
out with CALR and MPL drivers would be valuable too.
OK, so summing it all up then. In summary, this work provides
compelling evidence that while JAK inhibitors are effective
tools for MTN management, they can paradoxically Dr. the
expansion of Ras mutated clones through JAK 2 inhibition,
(17:35):
ultimately leading to more aggressive disease in those
patients. It's a fascinating example of
cancers, adaptive resistance andthe intricate crosstalk between
on congenic pathways. It really highlights the need to
understand the entire molecular landscape of a patient's tumor,
not just the most obvious drivermutation.
This feels like a critical step toward truly predictive
precision medicine. What does this mean for how we
(17:55):
need to think about monitoring and adapting treatments moving
forward, not just in MPN but maybe across oncology?
It means we need to be vigilant,targeted therapies can change
the rules of the game mid course.
We need dynamic monitoring strategies, maybe using liquid
biopsies to track clonal evolution non invasively.
And we need to be ready to adapttreatment based on how the
cancer is responding and evolving, potentially
(18:17):
anticipating resistance mechanisms like this one.
It's about staying one step ahead in that chess match.
A challenging but crucial goal. This episode was based on an
Open Access article under the CCBY 4 Point O license.
You can find a direct link to the paper and the license in our
episode description. If you enjoyed this analysis,
the best way to support Base by Base is to subscribe or follow
(18:39):
in your favorite podcast app andleave us a five star rating.
It only takes a few seconds but makes a huge difference in
helping others discover the show.
Thanks for listening and join usnext time as we explore more
science base by Base.
Welcome to Base by Base, the paper cast that brings genomics
to you wherever you are. OK, so think about this for a
second. What if the very treatment, you
know, the one designed to fight cancer?
What if it actually helps other,maybe even more dangerous cells
survive? That's a provocative thought.
Right. Like, imagine a therapy.
(00:35):
It makes a patient feel better. Symptoms improve, definitely.
But underneath, it's silently letting a more aggressive
version of the disease maybe take hold.
It sounds, well, kind of paradoxical.
It does, but it's not just hypothetical.
We're talking about cancers, incredible almost scary ability
to adapt so that this constant chess game, you know, between
(00:56):
our treatments and the cancer evolving resistance and
sometimes the drug that helps can also well act as this
selective pressure, empowering new, maybe tougher mutations.
Exactly selecting for the fittest, even if fittest means
more dangerous for the patient. So today we're diving into a
really fascinating and, yeah, somewhat counterintuitive
discovery in the world of blood cancers.
(01:17):
It throws this whole idea of adaptive resistance into sharp
relief. It really does.
How could targeting one specificpathway lead to the the
outgrowth of another, potentially making the disease
even more aggressive? Stick around, you're about to
find out. This deep dive today is possible
thanks to some really groundbreaking work by a
collaborative team, mostly researchers from University of
(01:40):
Paris. Cite a PHP opera Saint Louis and
INSERM in France. Right, a strong French core.
But also with significant contributions from teams in the
US, Dana Farber Cancer Instituteand Boston Children's Hospital.
So a real international effort. Absolutely.
And you know, we should mention some key contributors like Nabi
Masla, Nina Kasi, Blondin Rue and the PI's overseeing it, Jean
(02:03):
Jacques Kalajian, Bruno Kasanat and Lena Benijiba.
Their work has really pushed forward our understanding of how
cancer clones, these different cell populations evolve under
targeted therapy pressure. Especially in myeloproliferative
neoplasms, right? Exactly MPN's.
That's the specific focus here. OK, let's set the stage a bit.
Proliferative neoplasms. MPN's.
What are these exactly? So MPN's are a group of chronic
(02:25):
blood cancers. Basically the bone marrow goes
into OverDrive and produces too many blood cells, red cells,
white cells, platelets, depending on the specific type.
And they're considered pre leukemic.
That's right. They have this potential,
unfortunately, to transform intomore aggressive diseases like
acute myeloid leukemia, AML, which is obviously much more
(02:46):
dangerous. And what drives these MPN's at
the molecular level? A lot of them are driven by
activating mutations in a key signaling pathway called the
JAXA debt pathway. Think of it like a communication
network inside the cell that tells it to grow and divide OK
and specific genes in that pathway like JK2C ALRMPL often
(03:06):
have mutations that basically get stuck in the on position.
So if the problem is an overactive JAXA debt pathway,
well, targeting it seems logical.
Which brings us to Jack's inhibitors like Ruxilotenib.
These came out about what, over a decade?
Ago, yeah, around that, that time and they really did change
the treatment landscape for MPN now.
So what was the immediate impact?
Well, Rexel Litanib for example,it's a JAK 12 inhibitor.
(03:29):
It was and still is fantastic atimproving quality of life.
It dramatically reduces symptoms, things like severe
fatigue, fevers, night sweats, and it shrinks those enlarged
spleens, which can be really uncomfortable for patients.
So definite symptomatic relief. Huge symptomatic relief.
But the question lingered about its long term impact.
(03:51):
Does it actually change the underlying disease?
Does it really improve overall survival across the board?
That's been more debated. Right.
So we have drugs that work well for symptoms.
But researchers suspected there might be more going on under the
hood, genetically speaking, especially with long term
treatment. Exactly.
The worry was, OK, we're hittingthe main driver of the JK
mutation, but is that pressure inadvertently helping other
(04:14):
cancer cells? Different clones with different
mutations? Are we accidentally changing the
genetic landscape in ways we didn't initially predict?
Like wedding one type of weed only to have another, maybe
worse one take over the garden. That's a pretty good analogy,
yeah. So how did this research team
tackle this complex question? What was their approach?
They use a really smart, multi pronged approach.
(04:36):
They didn't just rely on one type of evidence, they started
by looking at real world patientdata.
Okay, tell us about that cohort.They studied 143 patients with
myelofibrosis, which is the typeof MPN often associated with
scarring in the bone marrow, andcrucially, they split this
group. 72 patients had received rexultinib and 71 had not.
(04:57):
A treated group and a control group, essentially.
Right. And they didn't just look at one
point in time, they performed longitudinal molecular
evaluations. They used next generation
sequencing NGS to track the genetic changes in the cancer
cells over time for each patient.
So they could see how the mutation profile evolved.
Precisely. But here's where they went a
step further, and this is reallycool.
(05:18):
They use single cell DNA sequencing on actual patient
cells. Single cell.
Wow. Yeah.
This lets you see not just what mutations are present in the
whole tumor sample, but which specific mutations are in which
individual cells. It lets you map out the clonal
architecture of the different families of cancer cells and see
how those families grow or shrink over time with treatment.
That gives you incredible resolution, so you can see if,
(05:41):
say, a tiny population of cells with a certain mutation suddenly
starts expanding. Exactly.
It moves beyond just averages, but observation is one thing.
To understand the how the mechanism they needed
experiments. Right, you need to test
causality. What did they do in the lab?
They did a lot of in vitro work experiments and lab dishes using
established cancer cell lines like Hel and Yuki one which have
(06:03):
Jake mutations and also importantly patient derived
cells. And in vivo too.
Yes, also in vivo using mouse models.
This combination is powerful because you can control the
conditions very precisely in thelab and then see if the same
effects hold up in a living Organism.
What were they simulating in these experiments?
They ran pompetition assays. Basically they'd mix cells with,
(06:23):
say, Ras mutation together with cells that didn't have it, or
cells with just the original JAK2 mutation, and then expose them
to rexolodib. To see who wins out under drug
pressure. Exactly.
See which population thrives when JK signaling is blocked.
They even specifically knocked down the Jack 2 gene in some
experiments to really isolate the effect of inhibiting that
(06:44):
specific target. Very thorough.
And one more thing, they validated their findings using
large public data sets like the BEAT AML cohort.
This helps ensure their results aren't just specific to their
patient group, but might reflectA broader biological principle.
It adds a lot of confidence. OK, so really comprehensive
strategy, patient data, single cell analysis, lab experiments,
(07:05):
mouse models, large data set validation.
So what did all this uncover? What's the big finding about
Ruxilet and NIB? The headline finding is a really
strong and frankly concerning link between Ruxilet and NIB
treatment and the rise of mutations in the Ras pathway.
Res like NRS Krayeus, right? Those well known cancer genes.
Exactly. Those, yeah, Nres, Krayefs also
(07:27):
CBL, which is part of that pathway regulation.
They found that in the patients treated with Ruxilet and NIB,
there was a significant accumulation A clonal outgrowth
of cells carrying these Ras pathway mutations.
How significant? Get this in the ruxolidin of
treated patients, 28% of all thenew mutations they detected over
time were in the Ras pathway. Compare that to only 7% in the
(07:49):
untreated patients. Wow, OK, that's a four fold
difference. That's not subtle.
Not subtle at all. And it wasn't just about new
mutations appearing. They looked at the variant
allele frequency, basically whatpercentage of the cancer cells
carried an existing RES mutation.
Right. How dominant that clone was.
Exactly, and the VAF of these RES mutations significantly
increased only in the group getting rexilitinib.
(08:11):
This really points towards the drug actively selecting for
these RES mutated cells. And was this effect specific to
RES or did other mutations also increase?
It seemed pretty specific to theRas pathway.
They looked at other common mutations found in MPNS, like AS
XL1, and didn't see the same pattern of outgrowth
specifically linked to ruxilitinib treatment.
(08:32):
OK. So the drug seems to favor RES
mutated cells, Yeah. But the critical question is
what does that mean for the patients?
Does it affect their outcome? And that's where the findings
become really stark. Yes, it dramatically affected
patient prognosis, but here's the key twist Only when patients
were on rexilitinib. Only in the treated group.
Only in the treated group, if you had ARAS mutation and were
(08:55):
taking rexilitinib, your prognosis was significantly
worse, your overall survival waslower and your transformation
free survival was lower. Let's break that down.
Overall survival. Median overall survival for
rexilitinib patients with RES mutation was about 7.6 years.
For those on rexilinib without RES mutation, it was over 18.5
(09:15):
years. That's a.
Huge difference, more than double the survival time if you
didn't have that res mutation while on the drug.
A massive difference and transformation free survival.
Can you explain that one? Sure, that's the time until the
disease progresses into a more aggressive form, usually acute
myeloid leukemia, AML or milder spilastic syndrome.
MD's and the. Impact.
(09:35):
There was, if anything even moredramatic.
In the rexilutinib group, if youhad a RES mutation, you had a
47% chance of transforming to AML or MD's.
Nearly half. Nearly half.
But if you had a RES mutation and were not on rexilutinib,
your chance of transformation was only 17%.
OK. So the combination of the drug
in the RES mutation is particularly bad news for
(09:58):
disease progression. It strongly suggests the drug is
creating an environment where these res mutated clones don't
just survive, they actively thrive and drive the disease
towards a more aggressive state.Which is deeply concerning So
the drug creates the pressure, but how?
What's the actual mechanism? How does inhibiting Jake help
Ras? That's.
What their lab experiments helped figure out.
(10:20):
The ex vivo and in vivo work showed directly that rexilutinib
selects for these RES mutated clones.
These cells showed increased fitness.
They grew better, proliferated more, even when Jack stat
signaling was shut down by the drug.
So they didn't need the Jake pathway anymore.
It seems they became less reliant on it or found
workarounds, and the key workaround involved another
major signaling pathway, the MAPK pathway.
(10:42):
Which is often downstream of Ras.
Right. Yeah, exactly.
Ras activation typically triggers the MPK pathway, which
also drives cell growth and survival.
The researchers found that this resistance to rexilit NIB in RES
mutated cells depended on MEPK activation.
How do they? Show that.
Crucially, when they experimentally inhibited the MPK
pathway using MEK inhibitors, for example, the Rs mutated
(11:05):
cells suddenly became sensitive to rexilit NIB again.
Ah OK, so blocking Jake selects for res mutants.
These mutants rely on MAP PK, and if you block MBK 2, you
restore sensitivity to the J inhibitor that connects the
dots. It really does.
It shows that the MBK pathway isessential for these Ras clones
to thrive under ruxilitinib pressure.
(11:26):
But then there was another twist.
Wasn't there something about an inverse relationship with JK2
itself? Yes, this was perhaps the most
counterintuitive part. They found that activating the
Rasmat K pathway, for instance by overexpressing Nras, actually
led to decreased levels of JK2 mRNA and protein.
Wait, so turning on the Ras pathway turned down the JK
pathway component? Kind of looks that way.
And they saw hints of this in the patient data too.
(11:48):
Patients whose cancers had low JK2 expression tended to have
stronger signs of rasmakay pathway activity and more active
cell division. So what's the thinking behind
that? Why would that happen?
The hypothesis is fascinating. It involves something called
oncogene induced senescence or stress.
Basically, if a cancer gene likeRES becomes too active, it can
(12:09):
trigger cellular alarm bells that force the cell to stop,
dividing, or even self destruct.It's a built in safety
mechanism. The idea is that maybe the
baseline activity from the mutated JAK 2, even if it's
driving the cancer initially, might also contribute just
enough pathway activity to keep this oncogene induced stress
response partially active in cells that also have ARAS
(12:30):
mutation. It's like having two
accelerators push part way down is actually worse for the cell
than just one push down hard. So the Jak 2 activity is almost
protective in a weird way against the Ras mutation going
completely wild. Potentially yes.
So when you treat with ruxilitinib, you inhibit JAK,
you take away that break or thatsource of stress and that might
be what fully unleashes the proliferative potential of the
(12:53):
pre-existing RES mutation. The Ras mutation was already
there, maybe in a small clone, but it couldn't fully take off
until JAK 2 was inhibited. Wow, so inhibiting 1 oncogenic
pathway removes a restraint on another that is complex?
Deeply complex, it highlights just how interconnected these
signaling networks are and how cancer can exploit these
(13:14):
connections in unexpected ways. This.
Is truly a deep dive into cancers adaptability?
What are the big takeaways here for patients?
For researchers. I think the main take away is
that JAK 2 inhibition, while clearly beneficial for symptoms
in MPN's, isn't a free lunch. Molecular speaking.
It can create this specific selective pressure that favors
the outgrowth of res mutated clones.
(13:35):
And these clones are bad news. And these clones are associated
with worse outcomes, specifically disease
transformation and lower survival when under Jack
inhibition. It reveals the sort of
paranoxical mechanism where inhibiting 1 pathway allows
another oncogenic pathway which might have been suppressed or
held in check to really flourish.
(13:57):
You mentioned a Goldilocks principle earlier.
Yeah, it's almost like that. Maybe too much signaling through
both jackstat and rasmapic pathways triggers cell
senescence or death. But if you inhibit Jackstat, you
might bring the rasmapic signaling into a just right zone
where it can drive aggressive proliferation without tripping
those safety alarms. This feels like it has immediate
(14:17):
clinical relevance. It's not just interesting
biology. Absolutely.
It strongly argues for screeningMPN patients for pre-existing
Ras mutations before starting them on a Jack inhibitor like
rexaltinib. Forewarned is forearmed.
Exactly, and it also suggests that regular molecular
monitoring during treatment is crucial.
We need to watch out for these Ras clones emerging or
(14:37):
expanding. And if they do emerge, what
then? Well, that's the next challenge,
but this research points towardsrational combination strategies.
If the resistance depends on theMEPK pathway, maybe combining
the Jake inhibitor with MEK inhibitor which targets METK
could prevent or overcome this resistance.
And you said trials for that arealready happening.
(14:59):
Yes, clinical trials exploring Jplus MEK inhibition are
underway. This kind of preclinical
mechanistic work directly informs those next generation
trial designs. Does this principle inhibiting 1
pathway unleashing another potentially apply beyond MPNS?
The authors certainly suggest itmight.
Cancers where Ras pathway mutations are common, think
(15:20):
pancreatic cancer. Some lung cancers, Melanoma
could potentially exhibit similar dynamics if treated with
drugs that affect related pathways.
Could it explain some mixed results with Jake inhibitors and
solid tumors perhaps? It's possible, or even the
observation, that ruxilithinib has sometimes been linked to an
increased risk of certain aggressive skin cancers, which
often carry RES mutations. It underscores this major
(15:42):
challenge in cancer therapy. Cancer is an adaptive system.
You push it here, it bulges out there.
But we need to be really clear here.
Despite this finding, JAK inhibitors are still valuable
tools for MPN patients, aren't they?
Oh, absolutely. Crucial to emphasize that yes,
JK inhibitors like roxalitinib remain a cornerstone of therapy
(16:03):
for many MPN patients. They provide significant symptom
relief and may offer survival benefits for certain patient
groups. So this isn't about throwing the
baby out with the bathwater. Not at all.
It's about refining our approach.
It's about understanding the risks, identifying patients who
might be susceptible to this resistance mechanism, and
developing smarter strategies, maybe combinations, maybe closer
(16:25):
monitoring to maximize the benefit while minimizing the
potential downsides. It's about personalization.
And like all studies, this one had limitations that point
towards as future research directions.
Sure. As we mentioned, the patient
cohort analysis was retrospective, looking back at
records, which always carries potential biases.
For example, patients who got rexiletinib might have already
(16:47):
had more aggressive disease. Prospective studies are needed
to confirm these findings definitively.
Right, following patients forward in time.
Exactly. Also, the number of RES mutated
patients in the non rexiletinib group was relatively small,
which limits the statistical power for some comparisons.
And while their lab data hinted the selection might happen
regardless of the initial MPN driver mutation, J AK2C ALRMPLA
(17:11):
lot of the deep mechanistic workfocused on the JAK 2V-617-F
context. More research on how this plays
out with CALR and MPL drivers would be valuable too.
OK, so summing it all up then. In summary, this work provides
compelling evidence that while JAK inhibitors are effective
tools for MTN management, they can paradoxically Dr. the
expansion of Ras mutated clones through JAK 2 inhibition,
(17:35):
ultimately leading to more aggressive disease in those
patients. It's a fascinating example of
cancers, adaptive resistance andthe intricate crosstalk between
on congenic pathways. It really highlights the need to
understand the entire molecular landscape of a patient's tumor,
not just the most obvious drivermutation.
This feels like a critical step toward truly predictive
precision medicine. What does this mean for how we
(17:55):
need to think about monitoring and adapting treatments moving
forward, not just in MPN but maybe across oncology?
It means we need to be vigilant,targeted therapies can change
the rules of the game mid course.
We need dynamic monitoring strategies, maybe using liquid
biopsies to track clonal evolution non invasively.
And we need to be ready to adapttreatment based on how the
cancer is responding and evolving, potentially
(18:17):
anticipating resistance mechanisms like this one.
It's about staying one step ahead in that chess match.
A challenging but crucial goal. This episode was based on an
Open Access article under the CCBY 4 Point O license.
You can find a direct link to the paper and the license in our
episode description. If you enjoyed this analysis,
the best way to support Base by Base is to subscribe or follow
(18:39):
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Thanks for listening and join usnext time as we explore more
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