EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer

被引：345

作者：

Amodio, Vito ^{[1
,2
]}

Yaeger, Rona ^{[3
]}

Arcella, Pamela ^{[1
,2
]}

Cancelliere, Carlotta ^{[1
]}

Lamba, Simona ^{[1
]}

Lorenzato, Annalisa ^{[1
,2
]}

Arena, Sabrina ^{[1
,2
]}

Montone, Monica ^{[1
]}

Mussolin, Benedetta ^{[1
]}

Bian, Yu ^{[4
]}

Whaley, Adele ^{[4
]}

Pinnelli, Marika ^{[1
,2
]}

Murciano-Goroff, Yonina R. ^{[3
]}

Vakiani, Efsevia ^{[5
]}

Valeri, Nicola ^{[6
,7
]}

Liao, Wei-Li ^{[8
]}

Bhalkikar, Anuja ^{[8
]}

Thyparambil, Sheeno ^{[8
]}

Zhao, Hui-Yong ^{[4
,9
]}

de Stanchina, Elisa ^{[4
,9
]}

Marsoni, Silvia ^{[10
,11
]}

Siena, Salvatore ^{[10
,12
]}

Bertotti, Andrea ^{[1
,2
]}

Trusolino, Livio ^{[1
,2
]}

Li, Bob T. ^{[3
,13
]}

Rosen, Neal ^{[1
,14
]}

Di Nicolantonio, Federica ^{[1
,2
]}

Bardelli, Alberto ^{[1
,2
]}

Misale, Sandra ^{[4
]}

机构：

[1] Candiolo Canc Inst, FPO IRCCS, Turin, Italy

[2] Univ Torino, Dept Oncol, Turin, Italy

[3] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

[4] Mem Sloan Kettering Canc Ctr, Mol Pharmacol Program, New York, NY 10065 USA

[5] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[6] Inst Canc Res, Ctr Evolut & Canc, London, England

[7] Royal Marsden Hosp, Dept Med, London, England

[8] mProbe Inc, Rockville, MD USA

[9] Mem Sloan Kettering Canc Ctr, Antitumour Assessment Core Facil, New York, NY 10065 USA

[10] Grande Osped Metropolitano Niguarda, Niguarda Canc Ctr, Milan, Italy

[11] Inst FIRC Oncol Mol IFOM, Milan, Italy

[12] Univ Milan, Dept Oncol & Hematooncol, Milan, Italy

[13] Weill Cornell Med Coll, New York, NY USA

[14] Mem Sloan Kettering Canc Ctr, Ctr Mol Based Therapy, New York, NY 10065 USA

来源：

CANCER DISCOVERY | 2020年 / 10卷 / 08期

基金：

欧洲研究理事会;

关键词：

ACQUIRED-RESISTANCE; LANDSCAPE; CETUXIMAB; TRIAL; RAS;

D O I：

10.1158/2159-8290.CD-20-0187

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Most patients with KRAS(G12C)-mutant non-small cell lung cancer (NSCLC) experience clinical benefit from selective KRAS(G12C) inhibition, whereas patients with colorectal cancer bearing the same mutation rarely respond. To investigate the cause of the limited efficacy of KRAS(G12C) inhibitors in colorectal cancer, we examined the effects of AMG510 in KRAS(G12C) colorectal cancer cell lines. Unlike NSCLC cell lines, KRAS(G12C) colorectal cancer models have high basal receptor tyrosine kinase (RTK) activation and are responsive to growth factor stimulation. In colorectal cancer lines, KRAS(G12C) inhibition induces higher phospho-ERK rebound than in NSCLC cells. Although upstream activation of several RTKs interferes with KRAS(G12C) blockade, we identify EGFR signaling as the dominant mechanism of colorectal cancer resistance to KRAS(G12C) inhibitors. The combinatorial targeting of EGFR and KRAS(G12C) is highly effective in colorectal cancer cells and patient-derived organoids and xenografts, suggesting a novel therapeutic strategy to treat patients with KRAS(G12C) colorectal cancer. SIGNIFICANCE: The efficacy of KRAS(G12C)inhibitors in NSCLC and colorectal cancer is lineage-specific. RTK dependency and signaling rebound kinetics are responsible for sensitivity or resistance to KRAS(G12C) inhibition in colorectal cancer. EGFR and KRAS(G12C) should be concomitantly inhibited to overcome resistance to KRAS(G12C) blockade in colorectal tumors.

引用

页码：1129 / 1139

页数：11

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