Extensive preclinical validation of combined RMC-4550 and LY3214996 supports clinical investigation for KRAS mutant pancreatic cancer

• DOI: 10.1016/j.xcrm.2022.100815
• Publication Date: 2022-11-16T05:02:18Z
• Authors: Katrin J. Frank; Antonio Mulero-Sá...; Alexandra Berninger; Laura Ruiz-Cañas; Astrid Bosma; Kıvanç Görgülü; Nan Wu; Kalliope N. Diako...; Ezgi Kaya-Aksoy; Dietrich A. Ruess; Derya Kabacaoğlu; Fränze Schmidt; Larissa Kohlmann; Olaf van Tellingen; Bram Thijssen; Marieke van de Ven; Natalie Proost; Susanne Kossatz; Wolfgang A. Weber; Bruno Sainz; Rene Bernards; Hana Algül; Marina Lesina; Sara Mainardi
• Keywords: 0301 basic medicine; Clinical Trials as Topic; Inhibitors; 610; PDAC; Preclinical models; Pancreatic cancer; MAPK; Article; ddc:; 3. Good health; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); ERK; Mice; 03 medical and health sciences; Targeted therapies; Cell Line, Tumor; Kras; SHP2; Animals; Combination therapy; Protein Kinase Inhibitors; Carcinoma, Pancreatic Ductal

Over 90% of pancreatic cancers present mutations in KRAS, one the most common oncogenic drivers overall. Currently, KRAS mutant isoforms cannot be targeted directly. Moreover, targeting single RAS downstream effectors induces adaptive resistance mechanisms. We report here on combined inhibition SHP2, upstream using allosteric inhibitor RMC-4550 and ERK, LY3214996. This combination shows synergistic anti-cancer activity vitro, superior disruption MAPK pathway, increased apoptosis induction compared with single-agent treatments. In vivo, we demonstrate good tolerability efficacy combination, significant tumor regression multiple ductal adenocarcinoma (PDAC) mouse models. Finally, show evidence that 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) can used to assess early drug responses animal Based these results, will investigate this SHP2 ERK cancer (SHERPA; ClinicalTrials.gov: NCT04916236) clinical trial, enrolling patients KRAS-mutant PDAC.