美国德克萨斯大学西南医学中心Carlos L. Arteaga、Ariella B. Hanker等研究人员合作发现，TORC1过度激活驱动对HER2突变型癌症中泛HER酪氨酸激酶抑制剂那拉替尼的耐药性。这一研究成果于2020年1月23日在线发表在国际学术期刊《癌细胞》上。

Title: Hyperactivation of TORC1 Drives Resistance to the Pan-HER Tyrosine Kinase Inhibitor Neratinib in HER2-Mutant Cancers

Author: Dhivya R. Sudhan, Angel Guerrero-Zotano, Helen Won, Paula González Ericsson, Alberto Servetto, Mariela Huerta-Rosario, Dan Ye, Kyung-min Lee, Luigi Formisano, Yan Guo, Qi Liu, Lisa N. Kinch, Monica Red Brewer, Teresa Dugger, James Koch, Michael J. Wick, Richard E. Cutler, Alshad S. Lalani, Richard Bryce, Alan Auerbach, Ariella B. Hanker, Carlos L. Arteaga

Issue&Volume: January 23, 2020

Abstract: We developed neratinib-resistant HER2-mutant cancer cells by gradual dose escalation. RNA sequencing identified TORC1 signalingas an actionable mechanism of drug resistance. Primary and acquired neratinib resistancein HER2-mutant breast cancer patient-derived xenografts (PDXs) was also associated with TORC1hyperactivity. Genetic suppression of RAPTOR or RHEB ablated P-S6 and restored sensitivityto the tyrosine kinase inhibitor. The combination of the TORC1 inhibitor everolimusand neratinib potently arrested the growth of neratinib-resistant xenografts and organoidsestablished from neratinib-resistant PDXs. RNA and whole-exome sequencing revealedRAS-mediated TORC1 activation in a subset of neratinib-resistant models. DNA sequencingof HER2-mutant tumors clinically refractory to neratinib, as well as circulating tumor DNAprofiling of patients who progressed on neratinib, showed enrichment of genomic alterationsthat converge to activate the mTOR pathway.

DOI: 10.1016/j.ccell.2019.12.013

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30583-5