Journal article
A Preexisting Rare PIK3CA(E545K) Subpopulation Confers Clinical Resistance to MEK plus CDK4/6 Inhibition in NRAS Melanoma and Is Dependent on S6K1 Signaling
Cancer discovery, v 8(5), pp 556-567
01 May 2018
PMID: 29496665
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Combined MEK and CDK4/6 inhibition (MEKi + CDK4i) has shown promising clinical outcomes in patients with NRAS-mutant melanoma. 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 PIK3CA(E545K) mutation as conferring drug resistance. We demonstrate that PIK3CA(E545K) preexisted in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multiregion sampling due to PIK3CA(E545K) being nonuniformly 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 PIK3CA(E545K)-induced resistance. These results demonstrate that difficult-to-detect preexisting 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.
SIGNIFICANCE: We report the first characterization of clinical acquired resistance to MEKi + CDK4i, identifying a rare preexisting PIK3CA(E545K) subpopulation that expands upon therapy and exhibits drug resistance. We suggest that single-region pretreatment biopsy is insufficient to detect rare, spatially segregated drug-resistant subclones. Inhibition of S6K1 is able to resensitize PIK3CA(E545K)-expressing NRAS-mutant melanoma cells to MEKi + CDK4i. (C) 2018 AACR.
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Details
- Title
- A Preexisting Rare PIK3CA(E545K) Subpopulation Confers Clinical Resistance to MEK plus CDK4/6 Inhibition in NRAS Melanoma and Is Dependent on S6K1 Signaling
- Creators
- Gabriele Romano - Drexel University, Pharmacology and PhysiologyPei-Ling Chen - The University of Texas MD Anderson Cancer CenterPing Song - Rice UniversityJennifer L. McQuade - The University of Texas MD Anderson Cancer CenterRoger J. Liang - The University of Texas MD Anderson Cancer CenterMingguang Liu - The University of Texas MD Anderson Cancer CenterWhijae Roh - The University of Texas MD Anderson Cancer CenterDzifa Y. Duose - The University of Texas MD Anderson Cancer CenterFernando C. L. Carapeto - The University of Texas MD Anderson Cancer CenterJun Li - College Station Medical CenterJessica L. F. Teh - Thomas Jefferson Univ, Dept Canc Biol, Philadelphia, PA 19107 USAAndrew E. Aplin - Thomas Jefferson UniversityMerry Chen - The University of Texas MD Anderson Cancer CenterJianhua Zhang - The University of Texas MD Anderson Cancer CenterAlexander J. Lazar - The University of Texas MD Anderson Cancer CenterMichael A. Davies - College Station Medical CenterP. Andrew Futreal - The University of Texas MD Anderson Cancer CenterRodabe N. Amaria - The University of Texas MD Anderson Cancer CenterDavid Y. Zhang - Rice UniversityJennifer A. Wargo - The University of Texas MD Anderson Cancer CenterLawrence N. Kwong - The University of Texas MD Anderson Cancer Center
- Publication Details
- Cancer discovery, v 8(5), pp 556-567
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 12
- Grant note
- MD Anderson Melanoma Moon Shots Programs CA182635; 4P01 CA163222-04 / NIH/NCI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Dr. Miriam and Sheldon G. Adelson Medical Research Foundation CA-16672 / National Cancer Institute (NCI) Cancer Center Support Grant CPRIT; Cancer Prevention & Research Institute of Texas University of Texas Rising STARS award R01CA203964 / NCI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) 508743 / Melanoma Research Alliance Young Investigator Award
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000431293900021
- Scopus ID
- 2-s2.0-85047868606
- Other Identifier
- 991021965770404721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Oncology