@article{ea1c2408991348448868bbb1c1f12a5a,
title = "The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor–positive metastatic breast cancer",
abstract = "Mechanisms driving resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor–positive (HR+) breast cancer have not been clearly defined. Whole-exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, and loss of estrogen receptor expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA, or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Three of these activating alterations—in AKT1, RAS, and AURKA—have not, to our knowledge, been previously demonstrated as mechanisms of resistance to CDK4/6i in breast cancer preclinically or in patient samples. Together, these eight mechanisms were present in 66% of resistant tumors profiled and may define therapeutic opportunities in patients. Significance: We identified eight distinct mechanisms of resistance to CDK4/6i present in 66% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR+ metastatic breast cancer.",
author = "Wander, {Seth A.} and Ofir Cohen and Xueqian Gong and Johnson, {Gabriela N.} and Buendia-Buendia, {Jorge E.} and Lloyd, {Maxwell R.} and Dewey Kim and Flora Luo and Pingping Mao and Karla Helvie and Kowalski, {Kailey J.} and Utthara Nayar and Waks, {Adrienne G.} and Parsons, {Stephen H.} and Ricardo Martinez and Litchfield, {Lacey M.} and Ye, {Xiang S.} and Chunping Yu and Jansen, {Valerie M.} and Stille, {John R.} and Smith, {Patricia S.} and Oakley, {Gerard J.} and Chu, {Quincy S.} and Gerald Batist and Hughes, {Melissa E.} and Kremer, {Jill D.} and Garraway, {Levi A.} and Winer, {Eric P.} and Tolaney, {Sara M.} and Lin, {Nancy U.} and Buchanan, {Sean G.} and Nikhil Wagle",
note = "Funding Information: S.A. Wander is a consultant at Foundation Medicine, InfiniteMD, Eli Lilly, and Puma Biotechnology, and reports receiving commercial research support from Genentech. X. Gong is a researcher at Eli Lilly and Company, and has ownership interest (including patents) in Eli Lilly and Company. L.M. Litchfield is an employee at Eli Lilly and Company, and has ownership interest (including patents) in Eli Lilly and Company. V.M. Jansen is a senior medical advisor at and has ownership interest (including patents) in Eli Lilly and Company. G.J. Oakley is a senior medical advisor at Eli Lilly and Company. J.D. Kremer is a clinical research physician at Eli Lilly and medical director at Taiho Oncology Inc. E.P. Winer is a consultant at Carrick Therapeutics, G1 Therapeutics, Syros, Genentech, Genomic Health, GSK, Jounce, Leap, Lilly, Novartis, and Seattle Genetics. S.M. Tolaney is a consultant at AstraZeneca, Eli Lilly, Puma, Sanofi, Odonate, Seattle Genetics, Silverback Therapeutics, G1 Therapeutics, AbbVie, Anthenex, OncoPep, Merck, Nektar, Novartis, Pfizer, Genentech, Immunomedics, Bristol-Myers Squibb, and NanoString, and reports receiving commercial research grants from Merck (all funding to institute), Novartis (all funding to institute), Pfizer (all funding to institute), and Eli Lilly (all funding to institute). N.U. Lin reports receiving commercial research grants from Genentech, Seattle Genetics, Pfizer, and Merck, and is a consultant/advisory board member for Puma, Seattle Genetics, and Daichii Sankyo. S.G. Buchanan is a senior research fellow at Eli Lilly, and has ownership interest (including patents) in Eli Lilly. N. Wagle is a consultant/advisory board member at Eli Lilly, Novartis, and Relay Therapeutics, reports receiving a commercial research grant from Puma Biotechnology (all funding to institute), and has ownership interest (including patents) in Relay Therapeutics. No potential conflicts of interest were disclosed by the other authors. Funding Information: We thank Laura Dellostritto, Lori Marini, Nelly Oliver, Shreevidya Periyasamy, Janet Files, Sara Hoffman, and Colin Mackichan for assistance with patient sample collection and annotation. We are grateful to all the patients who volunteered for our tumor biopsy protocol and generously provided the tissue analyzed in this study. This work was supported by the Department of Defense W81XWH-13-1-0032 (to N. Wagle), Landon Foundation-AACR INNOVATOR Award for Research in Personalized Cancer Medicine, 13-60-27-WAGL (to N. Wagle), NCI Breast Cancer SPORE at DF/HCC #P50CA168504 (to N. Wagle, N.U. Lin, and E.P. Winer), Susan G. Komen CCR15333343 (to N. Wagle), The V Foundation (to N. Wagle), The Breast Cancer Alliance (to N. Wagle), The Cancer Couch Foundation (to N. Wagle), Twisted Pink (to N. Wagle), Hope Scarves (to N. Wagle), Breast Cancer Research Foundation (to N.U. Lin and E.P. Winer), ACT NOW (to Dana-Farber Cancer Institute Breast Oncology Program), Fashion Footwear Association of New York (to Dana-Farber Cancer Institute Breast Oncology Program), Friends of Dana-Farber Cancer Institute (to N. U. Lin), National Comprehensive Cancer Network/Pfizer Independent Grant for Learning & Change (to N.U. Lin), the Dana-Farber Cancer Institute T32 (to S.A. Wander), Wong Family Translational Research Award (to S.A. Wander), and the Conquer Cancer Foundation/Twisted Pink/American Society of Clinical Oncology Young Investigator Award (to S.A. Wander). Funding Information: We thank Laura Dellostritto, Lori Marini, Nelly Oliver, Shreevidya Periyasamy, Janet Files, Sara Hoffman, and Colin Mackichan for assistance with patient sample collection and annotation. We are grateful to all the patients who volunteered for our tumor biopsy protocol and generously provided the tissue analyzed in this study. This work was supported by the Department of Defense W81XWH-13-1-0032 (to N. Wagle), Landon Foundation-AACR INNOVATOR Award for Research in Personalized Cancer Medicine, 13-60-27-WAGL (to N. Wagle), NCI Breast Cancer SPORE at DF/HCC #P50CA168504 (to N. Wagle, N.U. Lin, and E.P. Winer), Susan G. Komen CCR15333343 (to N. Wagle), The V Foundation (to N. Wagle), The Breast Cancer Alliance (to N. Wagle), The Cancer Couch Foundation (to N. Wagle), Twisted Pink (to N. Wagle), Hope Scarves (to N. Wagle), Breast Cancer Research Foundation (to N.U. Lin and E.P. Winer), ACT NOW (to Dana-Farber Cancer Institute Breast Oncology Program), Fashion Footwear Association of New York (to Dana-Farber Cancer Institute Breast Oncology Program), Friends of Dana-Farber Cancer Institute (to N. U. Lin), National Comprehensive Cancer Network/Pfizer Independent Grant for Learning & Change (to N.U. Lin), the Dana-Farber Cancer Institute T32 (to S.A. Wander), Wong Family Translational Research Award (to S.A. Wander), and the Conquer Cancer Founda-tion/Twisted Pink/American Society of Clinical Oncology Young Investigator Award (to S.A. Wander). Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",
year = "2020",
month = aug,
day = "3",
doi = "https://doi.org/10.1158/2159-8290.CD-19-1390",
language = "English",
volume = "10",
pages = "1174--1193",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "John Wiley and Sons Inc.",
number = "8",
}
