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

Wasko, Urszula N.; Jiang, Jingjing; Dalton, Tanner C.; Curiel-Garcia, Alvaro; Edwards, A. Cole; Wang, Yingyun; Lee, Bianca; Orlen, Margo; Tian, Sha; Stalnecker, Clint A.; Drizyte-Miller, Kristina; Menard, Marie; Dilly, Julien; Sastra, Stephen A.; Palermo, Carmine F.; Hasselluhn, Marie C.; Decker-Farrell, Amanda R.; Chang, Stephanie; Jiang, Lingyan; Wei, Xing; Yang, Yu C.; Helland, Ciara; Courtney, Haley; Gindin, Yevgeniy; Muonio, Karl; Zhao, Ruiping; Kemp, Samantha B.; Clendenin, Cynthia; Sor, Rina; Vostrejs, William P.; Hibshman, Priya S.; Amparo, Amber M.; Hennessey, Connor; Rees, Matthew G.; Ronan, Melissa M.; Roth, Jennifer A.; Brodbeck, Jens; Tomassoni, Lorenzo; Bakir, Basil; Socci, Nicholas D.; Herring, Laura E.; Barker, Natalie K.; Wang, Junning; Cleary, James M.; Wolpin, Brian M.; Chabot, John A.; Kluger, Michael D.; Manji, Gulam A.; Tsai, Kenneth Y.; Sekulic, Miroslav; Lagana, Stephen M.; Califano, Andrea; Quintana, Elsa; Wang, Zhengping; Smith, Jacqueline A. M.; Holderfield, Matthew; Wildes, David; Lowe, Scott W.; Badgley, Michael A.; Aguirre, Andrew J.; Vonderheide, Robert H.; Stanger, Ben Z.; Baslan, Timour; Der, Channing J.; Singh, Mallika; Olive, Kenneth P.

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

Urszula N. Wasko, Jingjing Jiang, Tanner C. Dalton, Alvaro Curiel-Garcia, A. Cole Edwards, Yingyun Wang, Bianca Lee, Margo Orlen, Sha Tian, Clint A. Stalnecker, Kristina Drizyte-Miller, Marie Menard, Julien Dilly, Stephen A. Sastra, Carmine F. Palermo, Marie C. Hasselluhn, Amanda R. Decker-Farrell, Stephanie Chang, Lingyan Jiang, Xing Wei, Yu C. Yang, Ciara Helland, Haley Courtney, Yevgeniy Gindin, Karl Muonio, Ruiping Zhao, Samantha B. Kemp, Cynthia Clendenin, Rina Sor, William P. Vostrejs, Priya S. Hibshman, Amber M. Amparo, Connor Hennessey, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Jens Brodbeck, Lorenzo Tomassoni, Basil Bakir, Nicholas D. Socci, Laura E. Herring, Natalie K. Barker, Junning Wang, James M. Cleary, Brian M. Wolpin, John A. Chabot, Michael D. Kluger, Gulam A. Manji, Kenneth Y. Tsai, Miroslav Sekulic, Stephen M. Lagana, Andrea Califano, Elsa Quintana, Zhengping Wang, Jacqueline A. M. Smith, Matthew Holderfield, David Wildes, Scott W. Lowe, Michael A. Badgley, Andrew J. Aguirre, Robert H. Vonderheide, Ben Z. Stanger, Timour Baslan, Channing J. Der, Mallika Singh () and Kenneth P. Olive ()
Additional contact information
Urszula N. Wasko: Columbia University Irving Medical Center
Jingjing Jiang: Revolution Medicines
Tanner C. Dalton: Columbia University Irving Medical Center
Alvaro Curiel-Garcia: Columbia University Irving Medical Center
A. Cole Edwards: University of North Carolina at Chapel Hill
Yingyun Wang: Revolution Medicines
Bianca Lee: Revolution Medicines
Margo Orlen: Department of Medicine
Sha Tian: Memorial Sloan Kettering Cancer Center
Clint A. Stalnecker: University of North Carolina at Chapel Hill
Kristina Drizyte-Miller: University of North Carolina at Chapel Hill
Marie Menard: Revolution Medicines
Julien Dilly: Dana-Farber Cancer Institute
Stephen A. Sastra: Columbia University Irving Medical Center
Carmine F. Palermo: Columbia University Irving Medical Center
Marie C. Hasselluhn: Columbia University Irving Medical Center
Amanda R. Decker-Farrell: Columbia University Irving Medical Center
Stephanie Chang: Revolution Medicines
Lingyan Jiang: Revolution Medicines
Xing Wei: Revolution Medicines
Yu C. Yang: Revolution Medicines
Ciara Helland: Revolution Medicines
Haley Courtney: Revolution Medicines
Yevgeniy Gindin: Revolution Medicines
Karl Muonio: Revolution Medicines
Ruiping Zhao: Revolution Medicines
Samantha B. Kemp: Department of Medicine
Cynthia Clendenin: Abramson Cancer Center
Rina Sor: Abramson Cancer Center
William P. Vostrejs: Department of Medicine
Priya S. Hibshman: University of North Carolina at Chapel Hill
Amber M. Amparo: University of North Carolina at Chapel Hill
Connor Hennessey: Dana-Farber Cancer Institute
Matthew G. Rees: The Broad Institute of Harvard and MIT
Melissa M. Ronan: The Broad Institute of Harvard and MIT
Jennifer A. Roth: The Broad Institute of Harvard and MIT
Jens Brodbeck: Revolution Medicines
Lorenzo Tomassoni: Columbia University Irving Medical Center
Basil Bakir: Columbia University Irving Medical Center
Nicholas D. Socci: Memorial Sloan Kettering Cancer Center
Laura E. Herring: University of North Carolina at Chapel Hill
Natalie K. Barker: University of North Carolina at Chapel Hill
Junning Wang: Dana-Farber Cancer Institute
James M. Cleary: Dana-Farber Cancer Institute
Brian M. Wolpin: Dana-Farber Cancer Institute
John A. Chabot: Columbia University Irving Medical Center
Michael D. Kluger: Columbia University Irving Medical Center
Gulam A. Manji: Columbia University Irving Medical Center
Kenneth Y. Tsai: H. Lee Moffitt Cancer Center and Research Institute
Miroslav Sekulic: Columbia University Irving Medical Center
Stephen M. Lagana: Columbia University Irving Medical Center
Andrea Califano: Columbia University Irving Medical Center
Elsa Quintana: Revolution Medicines
Zhengping Wang: Revolution Medicines
Jacqueline A. M. Smith: Revolution Medicines
Matthew Holderfield: Revolution Medicines
David Wildes: Revolution Medicines
Scott W. Lowe: Memorial Sloan Kettering Cancer Center
Michael A. Badgley: Columbia University Irving Medical Center
Andrew J. Aguirre: Dana-Farber Cancer Institute
Robert H. Vonderheide: Department of Medicine
Ben Z. Stanger: Department of Medicine
Timour Baslan: The University of Pennsylvania
Channing J. Der: University of North Carolina at Chapel Hill
Mallika Singh: Revolution Medicines
Kenneth P. Olive: Columbia University Irving Medical Center

Nature, 2024, vol. 629, issue 8013, 927-936

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07379-z

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