Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer

  • Nature. 2024 May;629(8013):927-936. doi: 10.1038/s41586-024-07379-z.
Urszula N Wasko  #  1  2 ,  Jingjing Jiang  #  3 ,  Tanner C Dalton  1  2 ,  Alvaro Curiel-Garcia  1  2 ,  A Cole Edwards  4 ,  Yingyun Wang  3 ,  Bianca Lee  3 ,  Margo Orlen  5 ,  Sha Tian  6 ,  Clint A Stalnecker  7  8 ,  Kristina Drizyte-Miller  7 ,  Marie Menard  3 ,  Julien Dilly  9  10 ,  Stephen A Sastra  1  2 ,  Carmine F Palermo  1  2 ,  Marie C Hasselluhn  1  2 ,  Amanda R Decker-Farrell  1  2 ,  Stephanie Chang  3 ,  Lingyan Jiang  3 ,  Xing Wei  3 ,  Yu C Yang  3 ,  Ciara Helland  3 ,  Haley Courtney  3 ,  Yevgeniy Gindin  3 ,  Karl Muonio  3 ,  Ruiping Zhao  3 ,  Samantha B Kemp  5 ,  Cynthia Clendenin  11 ,  Rina Sor  11 ,  William P Vostrejs  5 ,  Priya S Hibshman  4 ,  Amber M Amparo  7 ,  Connor Hennessey  9  10 ,  Matthew G Rees  12 ,  Melissa M Ronan  12 ,  Jennifer A Roth  12 ,  Jens Brodbeck  3 ,  Lorenzo Tomassoni  2  13 ,  Basil Bakir  1  2 ,  Nicholas D Socci  14 ,  Laura E Herring  15 ,  Natalie K Barker  15 ,  Junning Wang  9  10 ,  James M Cleary  9  10 ,  Brian M Wolpin  9  10 ,  John A Chabot  16 ,  Michael D Kluger  16 ,  Gulam A Manji  1  2 ,  Kenneth Y Tsai  17  18 ,  Miroslav Sekulic  19 ,  Stephen M Lagana  19 ,  Andrea Califano  1  2  13  20  21  22  23  24 ,  Elsa Quintana  3 ,  Zhengping Wang  3 ,  Jacqueline A M Smith  3 ,  Matthew Holderfield  3 ,  David Wildes  3 ,  Scott W Lowe  6  25 ,  Michael A Badgley  1  2 ,  Andrew J Aguirre  9  10  12  26 ,  Robert H Vonderheide  5  11  27 ,  Ben Z Stanger  5  11 ,  Timour Baslan  28 ,  Channing J Der  7  8 ,  Mallika Singh  29 ,  Kenneth P Olive  30  31
Affiliations
  • 1. Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
  • 2. Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.
  • 3. Revolution Medicines, Redwood City, CA, USA.
  • 4. Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 5. University of Pennsylvania Perelman School of Medicine, Department of Medicine, Philadelphia, PA, USA.
  • 6. Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 7. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 8. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 9. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 10. Harvard Medical School, Boston, MA, USA.
  • 11. University of Pennsylvania Perelman School of Medicine, Abramson Cancer Center, Philadelphia, PA, USA.
  • 12. The Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • 13. Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA.
  • 14. Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 15. UNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 16. Department of Surgery, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
  • 17. Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
  • 18. Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
  • 19. Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
  • 20. Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 21. J. P. Sulzberger Columbia Genome Center, Columbia University, New York, NY, USA.
  • 22. Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, NY, USA.
  • 23. Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY, USA.
  • 24. Chan Zuckerberg Biohub New York, New York, NY, USA.
  • 25. Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 26. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
  • 27. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
  • 28. Department of Biomedical Sciences, School of Veterinary Medicine, The University of Pennsylvania, Philadelphia, PA, USA.
  • 29. Revolution Medicines, Redwood City, CA, USA. [email protected].
  • 30. Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. [email protected].
  • 31. Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA. [email protected].
  • # Contributed equally.
PMID: 38588697 DOI: 10.1038/s41586-024-07379-z
Abstract

Broad-spectrum Ras inhibition has the potential to benefit roughly a quarter of human patients with Cancer whose tumours are driven by Ras mutations1,2. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants3. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS4. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct Ras inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of Apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of Apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.

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