A preexisting rare PIK3CA e545k subpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling

Authors

Gabriele Romano, The University of Texas MD Anderson Cancer Center
Pei-Ling Chen, The University of Texas MD Anderson Cancer Center
Ping Song, Rice University
Jennifer L. McQuade, The University of Texas MD Anderson Cancer Center
Roger J. Liang, The University of Texas MD Anderson Cancer Center
Mingguang Liu, The University of Texas MD Anderson Cancer Center
Whijae Roh, The University of Texas MD Anderson Cancer Center
Dzifa Y. Duose, The University of Texas MD Anderson Cancer Center
Fernando C.L. Carapeto, The University of Texas MD Anderson Cancer Center
Jun Li, The University of Texas MD Anderson Cancer Center
Jessica L.F. Teh, Thomas Jefferson University
Andrew A. Aplin, Thomas Jefferson UniversityFollow
Merry Chen, The University of Texas MD Anderson Cancer Center
Jianhua Zhang, The University of Texas MD Anderson Cancer Center
Alexander J. Lazar, The University of Texas MD Anderson Cancer Center
Michael A. Davies, The University of Texas MD Anderson Cancer Center
P. Andrew Futreal, The University of Texas MD Anderson Cancer Center
Rodabe N. Amaria, The University of Texas MD Anderson Cancer Center
David Y. Zhang, Rice University
Jennifer A. Wargo, The University of Texas MD Anderson Cancer Center
Lawrence N. Kwong, The University of Texas MD Anderson Cancer Center

Document Type

Article

Publication Date

5-1-2018

Comments

This article has been peer reviewed. It is the authors' final version prior to publication in Cancer Discovery, Volume 8, Issue 5, May 2018, Pages 556-567.

The published version is available at https://doi.org/10.1158/2159-8290.CD-17-0745. Copyright © AACR

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. © 2018 AACR

Recommended Citation

Romano, Gabriele; Chen, Pei-Ling; Song, Ping; McQuade, Jennifer L.; Liang, Roger J.; Liu, Mingguang; Roh, Whijae; Duose, Dzifa Y.; Carapeto, Fernando C.L.; Li, Jun; Teh, Jessica L.F.; Aplin, Andrew A.; Chen, Merry; Zhang, Jianhua; Lazar, Alexander J.; Davies, Michael A.; Futreal, P. Andrew; Amaria, Rodabe N.; Zhang, David Y.; Wargo, Jennifer A.; and Kwong, Lawrence N., "A preexisting rare PIK3CA e545k subpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling" (2018). Department of Cancer Biology Faculty Papers. Paper 152.
https://jdc.jefferson.edu/cbfp/152

PubMed ID

29496665

Language

English