1. Molecular Characterization of Acquired Resistance to KRASG12C-EGFR Inhibition in Colorectal Cancer
- Author
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Rona Yaeger, Riccardo Mezzadra, Jenna Sinopoli, Yu Bian, Michelangelo Marasco, Esther Kaplun, Yijun Gao, HuiYong Zhao, Arnaud Da Cruz Paula, Yingjie Zhu, Almudena Chaves Perez, Kalyani Chadalavada, Edison Tse, Sudhir Chowdhry, Sydney Bowker, Qing Chang, Besnik Qeriqi, Britta Weigelt, Gouri J. Nanjangud, Michael F. Berger, Hirak Der-Torossian, Kenna Anderes, Nicholas D. Socci, Jinru Shia, Gregory J. Riely, Yonina R. Murciano-Goroff, Bob T. Li, James G. Christensen, Jorge S. Reis-Filho, David B. Solit, Elisa de Stanchina, Scott W. Lowe, Neal Rosen, and Sandra Misale
- Subjects
Oncology - 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.
- Published
- 2022
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