Abstract 1054: RAS-pathway inhibitors (Sotorasib, MRTX-1257, TNO-155, BI-3406) in a Complex Spheroid Combination Screen with PDMR Cell Lines
Authors: Takebe Naoko , Dexheimer Thomas , Silvers Thomas , Delosh Rene , Laudeman Julie , Paul Siddhartha , Reinhardt Russell , Ogle Chad , Morris Joel , Coussens Nathan , Doroshow James H. , Teicher Beverly A. 
Published: June 2022

Abstract
The KRAS G12C selective inhibitors, sotorasib and MRTX-1257, as well as the SHP-2 inhibitor TNO-155 and the SOS-1 inhibitor were assayed alone and in combination with approved and investigational anticancer agents in complex spheroids including tumor cells, endothelial cells (HUVEC) and mesenchymal stem cells (MSCs). The cell lines were from the PDMR collection (https://pdmr.cancer.gov/models/database.htm). The Ras mutation status of each line was known and included KRAS G12C (5 lines), KRAS G12D (7 lines) and 8 lines which were RAS WT or harbored other RAS mutations. The high concentration range of each agent was near the clinical Cmax for the drug or was 10 μM and decreased in half-logs covering a 3-log range. The complex spheroids were established for 3 days before drug(s) were added. Seven days after drug exposure the experiment was terminated with CellTiter-Glo 3D. Cell viability was determined relative to a vehicle treated control and IC50 values were calculated from concentration response curves. The concentration response for sotorasib and MRTX-1257 (except for concentrations 3 μM or higher) inhibitors were shallow to flat. The 4 KRAS G12C mutant line were most sensitive to sotorasib and MRTX-1257 with the KRAS G12C mutant pancreatic cancer line being the next most sensitive. A similar pattern was observed with the SHP-2 inhibitor TNO-155; however, there was no selectivity for the KRAS G12C mutant lines in response to the SOS-1 inhibitor BI-3406. There was heterogeneity in the occurrence of additivity/synergy amongst the KRAS G12C mutant lines in the combination studies likely indicating that factors in addition to KRAS mutations influenced response. The most successful combination was TNO-155 plus ipatasertib which resulted in more than 1-log of cell kill in 9 of 20 lines including the 5 KRAS G12C mutant lines. Venetoclax in combination with the RAS pathway inhibitors was active in 4 of the 5 KRAS G12C lines as was the combination of sapanisertib and TNO-155. TNO-155 in combination with sotorasib, MRTX-1257 or BI-3406 was highly active in the LG0567-F671 NSCLC harboring KRAS G12C. The response of the RAS mutant lines to the combinations was compared with the response of RAS WT lines to the same combinations. Often at the higher concentrations of the drugs/investigational agents, lines without RAS mutations are responsive. Next steps include PDX studies with the same tumor models. This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261200800001E.
Citation Format: Naoko Takebe, Thomas Dexheimer, Thomas Silvers, Rene Delosh, Julie Laudeman, Siddhartha Paul, Russell Reinhardt, Chad Ogle, Joel Morris, Nathan Coussens, James H. Doroshow, Beverly A. Teicher. RAS-pathway inhibitors (Sotorasib, MRTX-1257, TNO-155, BI-3406) in a Complex Spheroid Combination Screen with PDMR Cell Lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1054.