Supplementary Figure S7 from AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients with MTAP-Deleted Cancers

Belmontes, Brian; Slemmons, Katherine K.; Su, Chun; Liu, Siyuan; Policheni, Antonia N.; Moriguchi, Jodi; Tan, Hong; Xie, Fang; Aiello, Daniel Andrew; Yang, Yajing; Lazaro, Raul; Aeffner, Famke; Rees, Matthew G.; Ronan, Melissa M.; Roth, Jennifer A.; Vestergaard, Mikkel; Cowland, Sanne; Andersson, Jan; Sarvary, Ian; Chen, Qing; Sharma, Pooja; Lopez, Patricia; Tamayo, Nuria; Pettus, Liping H.; Ghimire-Rijal, Sudipa; Mukund, Susmith; Allen, Jennifer R.; DeVoss, Jason; Coxon, Angela; Rodon, Jordi; Ghiringhelli, François; Penel, Nicolas; Prenen, Hans; Glad, Sanne; Chuang, Chen-Hua; Keyvanjah, Kiana; Townsley, Danielle M.; Butler, John R.; Bourbeau, Matthew P.; Caenepeel, Sean; Hughes, Paul E.

doi:10.1158/2159-8290.28193707

Supplementary Figure S7 from AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients with MTAP-Deleted Cancers

journal contribution

posted on 2025-01-13, 08:20 authored by Brian Belmontes, Katherine K. Slemmons, Chun Su, Siyuan Liu, Antonia N. Policheni, Jodi Moriguchi, Hong Tan, Fang Xie, Daniel Andrew Aiello, Yajing Yang, Raul Lazaro, Famke Aeffner, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Mikkel Vestergaard, Sanne Cowland, Jan Andersson, Ian Sarvary, Qing Chen, Pooja Sharma, Patricia Lopez, Nuria Tamayo, Liping H. Pettus, Sudipa Ghimire-Rijal, Susmith Mukund, Jennifer R. Allen, Jason DeVoss, Angela Coxon, Jordi Rodon, François Ghiringhelli, Nicolas Penel, Hans Prenen, Sanne Glad, Chen-Hua Chuang, Kiana Keyvanjah, Danielle M. Townsley, John R. Butler, Matthew P. Bourbeau, Sean Caenepeel, Paul E. Hughes

Supplementary Figure S7. Time course SDMA analysis, CDX models versus AMG 193, and AM-9747 PDX trial

History

ARTICLE ABSTRACT

One of the most robust synthetic lethal interactions observed in multiple functional genomic screens has been the dependency on protein arginine methyltransferase 5 (PRMT5) in cancer cells with MTAP deletion. We report the discovery of the clinical stage MTA-cooperative PRMT5 inhibitor AMG 193, which preferentially binds PRMT5 in the presence of MTA and has potent biochemical and cellular activity in MTAP-deleted cells across multiple cancer lineages. In vitro, PRMT5 inhibition induces DNA damage, cell cycle arrest, and aberrant alternative mRNA splicing in MTAP-deleted cells. In human cell line and patient-derived xenograft models, AMG 193 induces robust antitumor activity and is well tolerated with no impact on normal hematopoietic cell lineages. AMG 193 synergizes with chemotherapies or the KRAS G12C inhibitor sotorasib in vitro and combination treatment in vivo substantially inhibits tumor growth. AMG 193 is demonstrating promising clinical activity, including confirmed partial responses in patients with MTAP-deleted solid tumors from an ongoing phase 1/2 study.Significance: AMG 193 preferentially inhibits the growth of MTAP-deleted tumor cells by inhibiting PRMT5 when in complex with MTA, thus sparing MTAP wild-type normal cells. AMG 193 shows promise as a targeted therapy in a clinically defined patient population.