Details:

Alternative Title:
Cancer Discov
Personal Author:
Yaeger, Rona ; Mezzadra, Riccardo ; Sinopoli, Jenna ; Bian, Yu ; Marasco, Michelangelo ; ... More +
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 Less -
Description:
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.|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.
Subjects:
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Animals Colorectal Neoplasms Disease Models, Animal Drug Resistance, Neoplasm ErbB Receptors Humans Mutation Proto-Oncogene Proteins P21(ras) Signal Transduction
Source:
Cancer Discov. 13(1):41-55
Pubmed ID:
36355783
Pubmed Central ID:
PMC9827113
Document Type:
Journal Article
Funding:
U54 OD020355/OD/NIH HHSUnited States/ ; U54 OD020355/CD/ODCDC CDC HHSUnited States/ ; P30 CA008748/CA/NCI NIH HHSUnited States/ ; R01 CA233736/CA/NCI NIH HHSUnited States/
U54 OD020355/OD/NIH HHSUnited States/ ; U54 OD020355/CD/ODCDC CDC HHSUnited States/ ; P30 CA008748/CA/NCI NIH HHSUnited States/ ; R01 CA233736/CA/NCI NIH HHSUnited States/ Less -
Collection(s):
CDC Public Access
Main Document Checksum:
[+]
urn:sha256:bc1dd2cd1567281a8ea5fc4f9e9ae360818165e03c6cbf6dd35f590efa27a0b4
Download URL:
https://stacks.cdc.gov/view/cdc/123812/cdc_123812_DS1.pdf
File Type:

Supporting Files

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  	NIHMS1851493-supplement-9.pdf	pdf
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