Although oncogenic driver mutations in RAS occur in 20% of cancers, heterogeneity in the biologic outputs of different RAS mutants has hampered efforts to develop effective treatments for RAS-mutated cancers. In this issue of Science Signaling, Huynh et al. show that even among KRASQ61 mutants, the specific amino acid that is substituted substantially affects mutant KRAS biologic activity and oncogenicity.

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E. Sheffels, N. E. Sealover, C. Wang, D. H. Kim, I. A. Vazirani, E. Lee, E. M. Terrell, D. K. Morrison, J. Luo, R. L. Kortum, Oncogenic RAS isoforms show a hierarchical requirement for the guanine nucleotide exchange factor SOS2 to mediate cell transformation. Sci. Signal. 11, eaar8371 (2018).
E. M. Terrell, D. E. Durrant, D. A. Ritt, N. E. Sealover, E. Sheffels, R. Spencer-Smith, D. Esposito, Y. Zhou, J. F. Hancock, R. L. Kortum, D. K. Morrison, Distinct binding preferences between Ras and Raf family members and the impact on oncogenic Ras signaling. Mol. Cell 76, 872–884.e5 (2019).
J. C. Hunter, A. Manandhar, M. A. Carrasco, D. Gurbani, S. Gondi, K. D. Westover, Biochemical and structural analysis of common cancer-associated KRAS mutations. Mol. Cancer Res. 13, 1325–1335 (2015).
M. H. Hofmann, M. Gmachl, J. Ramharter, F. Savarese, D. Gerlach, J. R. Marszalek, M. P. Sanderson, D. Kessler, F. Trapani, H. Arnhof, K. Rumpel, D. A. Botesteanu, P. Ettmayer, T. Gerstberger, C. Kofink, T. Wunberg, A. Zoephel, S. C. Fu, J. L. Teh, J. Böttcher, N. Pototschnig, F. Schachinger, K. Schipany, S. Lieb, C. P. Vellano, J. C. O’Connell, R. L. Mendes, J. Moll, M. Petronczki, T. P. Heffernan, M. Pearson, D. McConnell, N. Kraut, BI-3406, a potent and selective SOS1-KRAS interaction inhibitor, is effective in KRAS-driven cancers through combined MEK inhibition. Cancer Discov. 11, 142–157 (2021).
C. W. Johnson, Y.-J. Lin, D. Reid, J. Parker, S. Pavlopoulos, P. Dischinger, C. Graveel, A. J. Aguirre, M. Steensma, K. M. Haigis, Isoform-specific destabilization of the active site reveals a molecular mechanism of intrinsic activation of KRas G13D. Cell Rep. 28, 1538–1550.e7 (2019).
J. H. Cook, G. E. M. Melloni, D. C. Gulhan, P. J. Park, K. M. Haigis, The origins and genetic interactions of KRAS mutations are allele- and tissue-specific. Nat. Commun. 12, 1808 (2021).
M. V. Huynh, G. A. Hobbs, A. Schaefer, M. Pierobon, L. M. Carey, J. N. Diehl, J. M. DeLiberty, R. D. Thurman, A. R. Cooke, C. M. Goodwin, J. H. Cook, L. Lin, A. M. Waters, N. U. Rashid, E. F. Petricoin III, S. L. Campbell, K. M. Haigis, D. M. Simeone, C. A. Lyssiotis, A. D. Cox, C. J. Der, Functional and biological heterogeneity of KRASQ61 mutations. Sci. Signal. 15, eabn2694 (2022).
Y. Kobayashi, C. Chhoeu, J. Li, K. S. Price, L. A. Kiedrowski, J. L. Hutchins, A. I. Hardin, Z. Wei, F. Hong, M. Bahcall, P. C. Gokhale, P. A. Jänne, Silent mutations reveal therapeutic vulnerability in RAS Q61 cancers. Nature 603, 335–342 (2022).
G. A. Hobbs, N. M. Baker, A. M. Miermont, R. D. Thurman, M. Pierobon, T. H. Tran, A. O. Anderson, A. M. Waters, J. N. Diehl, B. Papke, R. G. Hodge, J. E. Klomp, C. M. Goodwin, J. M. DeLiberty, J. Wang, R. W. S. Ng, P. Gautam, K. L. Bryant, D. Esposito, S. L. Campbell, E. F. Petricoin III, D. K. Simanshu, A. J. Aguirre, B. M. Wolpin, K. Wennerberg, U. Rudloff, A. D. Cox, C. J. der, Atypical KRASG12R mutant is impaired in PI3K signaling and macropinocytosis in pancreatic cancer. Cancer Discov. 10, 104–123 (2020).
S. Li, C. M. Counter, Signaling levels mold the RAS mutation tropism of urethane. eLife 10, e67172 (2021).

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Science Signaling
Volume 15 | Issue 746
August 2022

Submission history

Received: 13 June 2022
Accepted: 15 July 2022


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We thank B. Daley for comments and reading of the manuscript.
Funding: The Kortum laboratory is supported by funding from the NCI (1R01CA255232 and 1R21CA267515), the CDMRP Lung Cancer Research Program (LC180213 and LC210123), and a CRADA from Boehringer Ingelheim. The opinions and assertions expressed herein are those of the authors and are not to be construed as reflecting the views of Uniformed Services University of the Health Sciences or the United States Department of Defense.
Competing interests: The Kortum laboratory receives funding from Boehringer Ingelheim to study SOS1 as a therapeutic target in RAS-mutated cancers.



Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Roles: Conceptualization, Investigation, Methodology, Visualization, Writing - original draft, and Writing - review & editing.
Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Roles: Conceptualization, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, and Writing - review & editing.


Corresponding author. Email: [email protected]

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