In a recent study, Wasko et al. investigates the pharmacology and anti-tumor activity of RMC-7977, a multi-selective inhibitor targeting active, GTP-bound RAS family proteins (a RAS(ON) inhibitor), in preclinical models of pancreatic ductal adenocarcinoma (PDAC). RMC-7977 consistently and significantly inhibited RAS pathway signaling across PDAC cell lines, patient-derived organoids, and human tumor explants, leading to growth attenuation and/or the induction of apoptosis.

RMC-7977 exhibited marked tumor selectivity, with minimal effects on normal tissues expressing wild-type RAS. The study demonstrates that broad RAS-GTP inhibition induces tumor regressions and significantly extends survival in highly chemoresistant PDAC mouse models. Furthermore, the researchers identified MYC alterations as a potential mechanism of resistance to RMC-7977, suggesting combined targeting of the RAS and YAP–TAZ–TEAD pathways as a potential strategy for treating resistant tumors.

This study highlights the therapeutic potential of multi-selective RAS(ON) inhibitors in PDAC and other RAS-addicted cancers.

An IonOpticks Aurora Elite XT 15×75 C18 UHPLC column was used to better separate samples during LC-MS/MS analysis.

Publication
Nature

Authors

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 & Kenneth P. Olive

Title

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