Molecular Characterization of Acquired Resistance to KRASG12C-EGFR Inhibition in Colorectal Cancer

Yaeger, Rona, Mezzadra, Riccardo, Sinopoli, Jenna, Bian, Yu, Marasco, Michelangelo, Kaplun, Esther, Gao, Yijun, Zhao, HuiYong, Paula, Arnaud Da Cruz, Zhu, Yingjie, Perez, Almudena Chaves, Chadalavada, Kalyani, Tse, Edison, Chowdhry, Sudhir, Bowker, Sydney, Chang, Qing, Qeriqi, Besnik, Weigelt, Britta, Nanjangud, Gouri J, Berger, Michael F, Der-Torossian, Hirak, Anderes, Kenna, Socci, Nicholas D, Shia, Jinru, Riely, Gregory J, Murciano-Goroff, Yonina R, Li, Bob T, Christensen, James G, Reis-Filho, Jorge S, Solit, David B, de Stanchina, Elisa, Lowe, Scott W, Rosen, Neal, Misale, Sandra (January 2023) Molecular Characterization of Acquired Resistance to KRASG12C-EGFR Inhibition in Colorectal Cancer. Cancer Discovery, 13 (1). pp. 41-55. ISSN 2159-8274

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Abstract

With the combination of KRASG12C and EGFR inhibitors, KRAS is becoming a druggable target in colorectal cancer. However, secondary resistance limits its efficacy. Using cell lines, patient-derived xenografts, and patient samples, we detected a heterogeneous pattern of putative resistance alterations expected primarily to prevent inhibition of ERK signaling by drugs at progression. Serial analysis of patient blood samples on treatment demonstrates that most of these alterations are detected at a low frequency except for KRASG12C amplification, a recurrent resistance mechanism that rises in step with clinical progression. Upon drug withdrawal, resistant cells with KRASG12C amplification undergo oncogene-induced senescence, and progressing patients experience a rapid fall in levels of this alteration in circulating DNA. In this new state, drug resumption is ineffective as mTOR signaling is elevated. However, our work exposes a potential therapeutic vulnerability, whereby therapies that target the senescence response may overcome acquired resistance. SIGNIFICANCE: Clinical resistance to KRASG12C-EGFR inhibition primarily prevents suppression of ERK signaling. Most resistance mechanisms are subclonal, whereas KRASG12C amplification rises over time to drive a higher portion of resistance. This recurrent resistance mechanism leads to oncogene-induced senescence upon drug withdrawal and creates a potential vulnerability to senolytic approaches. This article is highlighted in the In This Issue feature, p. 1.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > neoplasms organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions diseases & disorders > cancer > cancer types > colon cancer diseases & disorders > cancer > cancer types > colon cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene organs, tissues, organelles, cell types and functions organs, tissues, organelles, cell types and functions > tissues types and functions > signal transduction organs, tissues, organelles, cell types and functions > tissues types and functions diseases & disorders > cancer > cancer types
CSHL Authors:	Lowe, Scott W.
Communities:	CSHL labs > Lowe lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	9 January 2023
Date Deposited:	02 Oct 2023 17:55
Last Modified:	11 Jan 2024 14:56
PMCID:	PMC9827113
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41097

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