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Diverse alterations associated with resistance to KRAS(G12C) inhibition

Author

Listed:
  • Yulei Zhao

    (Memorial Sloan Kettering Cancer)

  • Yonina R. Murciano-Goroff

    (Memorial Sloan Kettering Cancer Center)

  • Jenny Y. Xue

    (Memorial Sloan Kettering Cancer
    Weill Cornell–Rockefeller–Sloan Kettering Tri-Institutional MD-PhD Program)

  • Agnes Ang

    (Amgen)

  • Jessica Lucas

    (Memorial Sloan Kettering Cancer)

  • Trang T. Mai

    (Memorial Sloan Kettering Cancer)

  • Arnaud F. Cruz Paula

    (Memorial Sloan Kettering Cancer Center)

  • Anne Y. Saiki

    (Amgen)

  • Deanna Mohn

    (Amgen)

  • Pragathi Achanta

    (Amgen)

  • Ann E. Sisk

    (Memorial Sloan Kettering Cancer Center)

  • Kanika S. Arora

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Rohan S. Roy

    (Weill Cornell–Rockefeller–Sloan Kettering Tri-Institutional MD-PhD Program)

  • Dongsung Kim

    (Memorial Sloan Kettering Cancer)

  • Chuanchuan Li

    (Memorial Sloan Kettering Cancer)

  • Lee P. Lim

    (Resolution Bioscience)

  • Mark Li

    (Resolution Bioscience)

  • Amber Bahr

    (Memorial Sloan Kettering Cancer Center)

  • Brian R. Loomis

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Elisa Stanchina

    (Memorial Sloan Kettering Cancer Center)

  • Jorge S. Reis-Filho

    (Memorial Sloan Kettering Cancer Center)

  • Britta Weigelt

    (Memorial Sloan Kettering Cancer Center)

  • Michael Berger

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Gregory Riely

    (Memorial Sloan Kettering Cancer Center)

  • Kathryn C. Arbour

    (Memorial Sloan Kettering Cancer Center)

  • J. Russell Lipford

    (Amgen)

  • Bob T. Li

    (Memorial Sloan Kettering Cancer Center)

  • Piro Lito

    (Memorial Sloan Kettering Cancer
    Memorial Sloan Kettering Cancer Center
    Weill Cornell–Rockefeller–Sloan Kettering Tri-Institutional MD-PhD Program
    Weill Cornell Medical College)

Abstract

Inactive state-selective KRAS(G12C) inhibitors1–8 demonstrate a 30–40% response rate and result in approximately 6-month median progression-free survival in patients with lung cancer9. The genetic basis for resistance to these first-in-class mutant GTPase inhibitors remains under investigation. Here we evaluated matched pre-treatment and post-treatment specimens from 43 patients treated with the KRAS(G12C) inhibitor sotorasib. Multiple treatment-emergent alterations were observed across 27 patients, including alterations in KRAS, NRAS, BRAF, EGFR, FGFR2, MYC and other genes. In preclinical patient-derived xenograft and cell line models, resistance to KRAS(G12C) inhibition was associated with low allele frequency hotspot mutations in KRAS(G12V or G13D), NRAS(Q61K or G13R), MRAS(Q71R) and/or BRAF(G596R), mirroring observations in patients. Single-cell sequencing in an isogenic lineage identified secondary RAS and/or BRAF mutations in the same cells as KRAS(G12C), where they bypassed inhibition without affecting target inactivation. Genetic or pharmacological targeting of ERK signalling intermediates enhanced the antiproliferative effect of G12C inhibitor treatment in models with acquired RAS or BRAF mutations. Our study thus suggests a heterogenous pattern of resistance with multiple subclonal events emerging during G12C inhibitor treatment. A subset of patients in our cohort acquired oncogenic KRAS, NRAS or BRAF mutations, and resistance in this setting may be delayed by co-targeting of ERK signalling intermediates. These findings merit broader evaluation in prospective clinical trials.

Suggested Citation

  • Yulei Zhao & Yonina R. Murciano-Goroff & Jenny Y. Xue & Agnes Ang & Jessica Lucas & Trang T. Mai & Arnaud F. Cruz Paula & Anne Y. Saiki & Deanna Mohn & Pragathi Achanta & Ann E. Sisk & Kanika S. Arora, 2021. "Diverse alterations associated with resistance to KRAS(G12C) inhibition," Nature, Nature, vol. 599(7886), pages 679-683, November.
  • Handle: RePEc:nat:nature:v:599:y:2021:i:7886:d:10.1038_s41586-021-04065-2
    DOI: 10.1038/s41586-021-04065-2
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    Citations

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    Cited by:

    1. Irati Macaya & Marta Roman & Connor Welch & Rodrigo Entrialgo-Cadierno & Marina Salmon & Alba Santos & Iker Feliu & Joanna Kovalski & Ines Lopez & Maria Rodriguez-Remirez & Sara Palomino-Echeverria & , 2023. "Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Dan Lu & Yuan Chen & Min Jiang & Jie Wang & Yiting Li & Keke Ma & Wenqiao Sun & Xing Zheng & Jianxun Qi & Wenjing Jin & Yu Chen & Yan Chai & Catherine W. H. Zhang & Hao Liang & Shuguang Tan & George F, 2023. "KRAS G12V neoantigen specific T cell receptor for adoptive T cell therapy against tumors," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Haochen Zhang & Elias-Ramzey Karnoub & Shigeaki Umeda & Ronan Chaligné & Ignas Masilionis & Caitlin A. McIntyre & Palash Sashittal & Akimasa Hayashi & Amanda Zucker & Katelyn Mullen & Jungeui Hong & A, 2023. "Application of high-throughput single-nucleus DNA sequencing in pancreatic cancer," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Chi Zhou & Wenxin Li & Zhenxing Liang & Xianrui Wu & Sijing Cheng & Jianhong Peng & Kaixuan Zeng & Weihao Li & Ping Lan & Xin Yang & Li Xiong & Ziwei Zeng & Xiaobin Zheng & Liang Huang & Wenhua Fan & , 2024. "Mutant KRAS-activated circATXN7 fosters tumor immunoescape by sensitizing tumor-specific T cells to activation-induced cell death," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    5. Hidenori Kitai & Philip H. Choi & Yu C. Yang & Jacob A. Boyer & Adele Whaley & Priya Pancholi & Claire Thant & Jason Reiter & Kevin Chen & Vladimir Markov & Hirokazu Taniguchi & Rui Yamaguchi & Hiromi, 2024. "Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    6. Marie-Julie Nokin & Alessia Mira & Enrico Patrucco & Biagio Ricciuti & Sophie Cousin & Isabelle Soubeyran & Sonia San José & Serena Peirone & Livia Caizzi & Sandra Vietti Michelina & Aurelien Bourdon , 2024. "RAS-ON inhibition overcomes clinical resistance to KRAS G12C-OFF covalent blockade," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    7. Johanna Lilja & Jasmin Kaivola & James R. W. Conway & Joni Vuorio & Hanna Parkkola & Pekka Roivas & Michal Dibus & Megan R. Chastney & Taru Varila & Guillaume Jacquemet & Emilia Peuhu & Emily Wang & U, 2024. "SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    8. Ashenafi Bulle & Peng Liu & Kuljeet Seehra & Sapana Bansod & Yali Chen & Kiran Zahra & Vikas Somani & Iftikhar Ali Khawar & Hung-Po Chen & Paarth B. Dodhiawala & Lin Li & Yutong Geng & Chia-Kuei Mo & , 2024. "Combined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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