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The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor positive metastatic breast cancer

By Seth A Wander, Ofir Cohen, Xueqian Gong, Gabriela N. Johnson, Jorge Buendia-Buendia, Maxwell R. Lloyd, Dewey Kim, Flora Luo, Pingping Mao, Karla Helvie, Kailey J Kowalski, Utthara Nayar, Adrienne G Waks, Stephen Parsons, Ricardo Martinez, Lacey M. Litchfield, Xiang S. Ye, Chun Ping Yu, Valerie M. Jansen, John R. Stille, Patricia S. Smith, Gerard J. Oakley, Quincy Chu, Gerald Batist, Melissa Hughes, Jill D. Kremer, Levi A. Garraway, Eric P Winer, Sara M. Tolaney, Nancy U Lin, Sean Buchanan, Nikhil Wagle

Posted 28 Nov 2019
bioRxiv DOI: 10.1101/857839 (published DOI: 10.1158/2159-8290.CD-19-1390)

Clinical resistance mechanisms to CDK4/6 inhibitors in HR+ breast cancer have not been clearly 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 ER 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. Besides inactivation of RB1, which accounts for ~5% of resistance, seven of these mechanisms have not been previously identified as clinical mediators of resistance to CDK4/6 inhibitors in patients. Three of these - RAS activation, AKT activation, and AURKA activation - have not to our knowledge been previously demonstrated preclinically. Together, these eight mechanisms were present in 80% of resistant tumors profiled and may define therapeutic opportunities in patients.

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