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

作者：Alison Elizabeth Smith, Emanuela Ferraro, Anton Mikhailovich Safonov, Cristina Bernadó Morales, Enrique Javier Arenas, Qing Li, Amanda R. Kulick, Dara S. Ross, David B. Solit, Elisa de Stanchina, Jorge Sergio Reis-Filho, Neal X. Rosen, Joaquı́n Arribas, Pedram Razavi, Sarat Chandarlapaty · 发表于：Nature Communications · 年份：2021 · DOI：10.1038/s41467-021-27093-y · 被引用次数：91 · 研究领域：HER2/EGFR in Cancer Research、Melanoma and MAPK Pathways、PI3K/AKT/mTOR signaling in cancer

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.