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

Alison E. Smith, Emanuela Ferraro, Anton Safonov, Cristina Bernado Morales, Enrique J. Arenas Lahuerta, Qing Li, Amanda Kulick, Dara Ross, David B. Solit, Elisa Stanchina, Jorge Reis-Filho, Neal Rosen, Joaquín Arribas, Pedram Razavi and Sarat Chandarlapaty ()
Additional contact information
Alison E. Smith: Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center
Emanuela Ferraro: Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center
Anton Safonov: Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center
Cristina Bernado Morales: Preclinical Research Program, Vall d’Hebron Institute of Oncology
Enrique J. Arenas Lahuerta: Preclinical Research Program, Vall d’Hebron Institute of Oncology
Qing Li: Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center
Amanda Kulick: Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center
Dara Ross: Memorial Sloan Kettering Cancer Center
David B. Solit: Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center
Elisa Stanchina: Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center
Jorge Reis-Filho: Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center
Neal Rosen: Molecular Pharmacology and Chemistry Program and Center for Cell Engineering, Memorial Sloan Kettering Cancer Center
Joaquín Arribas: Preclinical Research Program, Vall d’Hebron Institute of Oncology
Pedram Razavi: Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center
Sarat Chandarlapaty: Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27093-y

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