2. Academic Validation
  3. Ras-mutant cancers are sensitive to small molecule inhibition of V-type ATPases in mice

Ras-mutant cancers are sensitive to small molecule inhibition of V-type ATPases in mice

  • Nat Biotechnol. 2022 Jul 25. doi: 10.1038/s41587-022-01386-z.
Bhairavi Tolani 1,  Anna Celli 2,  Yanmin Yao 3,  Yong Zi Tan 4 5 6,  Richard Fetter 7,  Christina R Liem 8 9,  Adam J de Smith 10,  Thamiya Vasanthakumar 4 11,  Paola Bisignano 3,  Adam D Cotton 3,  Ian B Seiple 3,  John L Rubinstein 4 11 12,  Marco Jost 13 14 15,  Jonathan S Weissman 8 16 17 18 19
Affiliations

Affiliations

  • 1 Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA. Bhairavi.Tolani@ucsf.edu.
  • 2 Laboratory for Cell Analysis Core Facility, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
  • 3 Department of Pharmaceutical Chemistry and Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
  • 4 Molecular Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.
  • 5 Department of Biological Sciences, National University of Singapore, Singapore, Singapore.
  • 6 Disease Intervention Technology Laboratory, Agency for Science, Technology and Research, Singapore, Singapore.
  • 7 Howard Hughes Medical Institute, Department of Biology, Stanford University, Stanford, CA, USA.
  • 8 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
  • 9 Division of Biological Sciences, the Section of Cell and Developmental Biology, University of California San Diego, La Jolla, CA, USA.
  • 10 Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA.
  • 11 Department of Biochemistry, The University of Toronto, Toronto, ON, Canada.
  • 12 Department of Medical Biophysics, The University of Toronto, Toronto, ON, Canada.
  • 13 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. marco_jost@hms.harvard.edu.
  • 14 Department of Microbiology & Immunology, University of California, San Francisco, CA, USA. marco_jost@hms.harvard.edu.
  • 15 Department of Microbiology, Harvard Medical School, Boston, MA, USA. marco_jost@hms.harvard.edu.
  • 16 Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 17 Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 18 David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 19 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
PMID: 35879364 DOI: 10.1038/s41587-022-01386-z
Abstract

Mutations in Ras family proteins are implicated in 33% of human cancers, but direct pharmacological inhibition of Ras mutants remains challenging. As an alternative to direct inhibition, we screened for sensitivities in Ras-mutant cells and discovered 249C as a Ras-mutant selective cytotoxic agent with nanomolar potency against a spectrum of Ras-mutant cancers. 249C binds to vacuolar (V)-ATPase with nanomolar affinity and inhibits its activity, preventing lysosomal acidification and inhibiting Autophagy and macropinocytosis pathways that several Ras-driven cancers rely on for survival. Unexpectedly, potency of 249C varies with the identity of the Ras driver mutation, with the highest potency for KRASG13D and G12V both in vitro and in vivo, highlighting a mutant-specific dependence on macropinocytosis and lysosomal pH. Indeed, 249C potently inhibits tumor growth without adverse side effects in mouse xenografts of KRAS-driven lung and colon cancers. A comparison of isogenic SW48 xenografts with different KRAS mutations confirmed that KRASG13D/+ (followed by G12V/+) mutations are especially sensitive to 249C treatment. These data establish proof-of-concept for targeting V-ATPase in cancers driven by specific KRAS mutations such as KRASG13D and G12V.

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