Synapse - HER2 + breast cancers evade anti-HER2 therapy via a switch in driver pathway

HER2 + breast cancers evade anti-HER2 therapy via a switch in driver pathway Journal Article

Authors:	Smith, A. E.; Ferraro, E.; Safonov, A.; Morales, C. B.; Lahuerta, E. J. A.; Li, Q.; Kulick, A.; Ross, D.; Solit, D. B.; de Stanchina, E.; Reis-Filho, J.; Rosen, N.; Arribas, J.; Razavi, P.; Chandarlapaty, S.
Article Title:	HER2 + breast cancers evade anti-HER2 therapy via a switch in driver pathway
Abstract:	Inhibition of HER2 in HER2-amplified breast cancer has been remarkably successful clinically, as demonstrated by the efficacy of HER-kinase inhibitors and HER2-antibody treatments. Whilst resistance to HER2 inhibition is common in the metastatic setting, the specific programs downstream of HER2 driving resistance are not established. Through genomic profiling of 733 HER2-amplified breast cancers, we identify enrichment of somatic alterations that promote MEK/ERK signaling in metastatic tumors with shortened progression-free survival on anti-HER2 therapy. These mutations, including NF1 loss and ERBB2 activating mutations, are sufficient to mediate resistance to FDA-approved HER2 kinase inhibitors including tucatinib and neratinib. Moreover, resistant tumors lose AKT dependence while undergoing a dramatic sensitization to MEK/ERK inhibition. Mechanistically, this driver pathway switch is a result of MEK-dependent activation of CDK2 kinase. These results establish genetic activation of MAPK as a recurrent mechanism of anti-HER2 therapy resistance that may be effectively combated with MEK/ERK inhibitors. © 2021, The Author(s).
Keywords:	survival; mutation; inhibitor; genomics; tumor; inhibition; antimicrobial activity; cancer
Journal Title:	Nature Communications
Volume:	12
Issue:	1
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Date Published:	2021-11-18
Start Page:	6667
Language:	English
DOI:	10.1038/s41467-021-27093-y
PROVIDER:	scopus
PUBMED:	34795269
PMCID:	PMC8602441
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85119258977&doi=10.1038%2fs41467-021-27093-y&partnerID=40&md5=5eb4390b9c18dd3014c7b3c473947351
Notes:	Article -- Export Date: 1 December 2021 -- Source: Scopus