Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition Journal Article


Authors: Xue, J. Y.; Zhao, Y.; Aronowitz, J.; Mai, T. T.; Vides, A.; Qeriqi, B.; Kim, D.; Li, C.; de Stanchina, E.; Mazutis, L.; Risso, D.; Lito, P.
Article Title: Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition
Abstract: KRAS GTPases are activated in one-third of cancers, and KRAS(G12C) is one of the most common activating alterations in lung adenocarcinoma1,2. KRAS(G12C) inhibitors3,4 are in phase-I clinical trials and early data show partial responses in nearly half of patients with lung cancer. How cancer cells bypass inhibition to prevent maximal response to therapy is not understood. Because KRAS(G12C) cycles between an active and inactive conformation4–6, and the inhibitors bind only to the latter, we tested whether isogenic cell populations respond in a non-uniform manner by studying the effect of treatment at a single-cell resolution. Here we report that, shortly after treatment, some cancer cells are sequestered in a quiescent state with low KRAS activity, whereas others bypass this effect to resume proliferation. This rapid divergent response occurs because some quiescent cells produce new KRAS(G12C) in response to suppressed mitogen-activated protein kinase output. New KRAS(G12C) is maintained in its active, drug-insensitive state by epidermal growth factor receptor and aurora kinase signalling. Cells without these adaptive changes—or cells in which these changes are pharmacologically inhibited—remain sensitive to drug treatment, because new KRAS(G12C) is either not available or exists in its inactive, drug-sensitive state. The direct targeting of KRAS oncoproteins has been a longstanding objective in precision oncology. Our study uncovers a flexible non-uniform fitness mechanism that enables groups of cells within a population to rapidly bypass the effect of treatment. This adaptive process must be overcome if we are to achieve complete and durable responses in the clinic. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.
Keywords: signal transduction; mitogen activated protein kinase; controlled study; oncoprotein; nonhuman; drug targeting; cell proliferation; animal cell; mouse; enzyme inhibition; protein targeting; epidermal growth factor receptor; animal experiment; animal model; enzyme activity; cell population; chemosensitivity; oncology; cancer cell; gefitinib; dactinomycin; k ras protein; enzyme specificity; cysteine; glycine; personalized medicine; enzyme conformation; adaptation; trametinib; afatinib; 8 [4 (1 aminocyclobutyl)phenyl] 9 phenyl 1,2,4 triazolo[3,4 f][1,6]naphthyridin 3(2h) one; aurora kinase; alisertib; female; priority journal; article; alpelisib; tozasertib; malignant neoplasm
Journal Title: Nature
Volume: 577
Issue: 7790
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2020-01-16
Start Page: 421
End Page: 425
Language: English
DOI: 10.1038/s41586-019-1884-x
PUBMED: 31915379
PROVIDER: scopus
PMCID: PMC7308074
DOI/URL:
Notes: Article -- Export Date: 3 February 2020 -- Source: Scopus
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Citation Impact
MSK Authors
  1. Piro Lito
    33 Lito
  2. Yaohua Xue
    8 Xue
  3. Alberto Vides
    4 Vides
  4. Thi Trang Mai
    5 Mai
  5. Besnik Qeriqi
    11 Qeriqi
  6. Linas Mazutis
    23 Mazutis
  7. Yulei Zhao
    4 Zhao
  8. Dongsung Kim
    4 Kim
  9. Chuanchuan Li
    3 Li