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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Aug 01, 2020
- Source ID
- 10.1158/2159-8290.cd-19-1390
Entities
People
- Adrienne G Waks
- Chunping Yu
- Dewey Kim
- Eric Winer
- Flora Luo
- Gabriela N. Johnson
- Gerald Batist
- Gerard J. Oakley
- Jill D. Kremer
- John R Stille
- Jorge E. Buendia-buendia
- Kailey J. Kowalski
- Karla Helvie
- Lacey M. Litchfield
- Levi A. Garraway
- Maxwell R Lloyd
- Melissa E. Hughes
- Nancy U Lin
- Nikhil Wagle
- Ofir Cohen
- Patricia S. Smith
- Pingping Mao
- Quincy S. Chu
- Ricardo Martinez
- Sara M Tolaney
- Sean G Buchanan
- Seth A. Wander
- Stephen H. Parsons
- Utthara Nayar
- Valerie M. Jansen
- Xiang S. Ye
- Xueqian Gong
Organizations
- American Association for Cancer Research
- Dana–Farber Cancer Institute
- McGill University
- National Cancer Institute
- Susan G. Komen for the Cure
- United States Department of Defense