A pre-existing rare PIK3CAE545K subpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling
Combined MEK and CDK4/6 inhibition (MEKi+CDK4i) has shown promising clinical outcomes in NRAS mutant melanoma patients. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi+CDK4i therapy but subsequently developed resistance. Whole exome sequencing and functional validation identified an acquired PIK3CAE545K mutation as conferring drug resistance. We demonstrate that PIK3CAE545K pre-existed in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multi-region sampling due to PIK3CAE545K being non-uniformly distributed. This resistant population rapidly expanded after the initiation of MEKi+CDK4i therapy and persisted in all successive samples even after immune checkpoint therapy and distant metastasis. Functional studies identified activated S6K1 as both a key marker and specific therapeutic vulnerability downstream of PIK3CAE545K-induced resistance. These results demonstrate that difficult-to-detect pre-existing resistance mutations may exist more often than previously appreciated and also posit S6K1 as a common downstream therapeutic nexus for the MAPK, CDK4/6, and PI3K pathways.
Pharmacology, Toxicology and Pharmaceutical Science
2
3%
Engineering
2
3%
Other
5
7%
Unknown
24
33%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 84. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 30 May 2018.
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#626,599
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#321
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#10,892
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Outputs of similar age from Cancer Discovery
#5
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Altmetric has tracked 32,890,663 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 98th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 4,662 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 24.0. This one has done particularly well, scoring higher than 93% of its peers.
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