Abstract 1105: MET or SHP2 inhibition enhances targeted therapies and delays the emergence of resistance in oncogene-driven NSCLC
Authors: Reischmann Nadine , Pudelko Lorenz , Stroh Christopher , Linde Nina , Musch Doreen , Keil Marina , Pudelko Linda , Esdar Christina , Blaukat Andree , Schumacher Karl M. , Karachaliou Niki 
Published: June 2022

Abstract
Background: Although advancements have been made in available targeted therapies for non-small cell lung cancer (NSCLC), most patients have an incomplete response and eventually acquire resistance. It is well known that MET signaling is a key pathway that mediates osimertinib resistance. Concurrently targeting multiple proteins in critical signaling pathways, including the MET receptor or SHP2, a key node downstream of receptor tyrosine kinases, may prevent or delay resistance. Here, we explore the promising concept of combining upfront targeted therapies with a selective MET inhibitor or SHP2 inhibitor as promising therapeutic strategies for oncogene-driven NSCLC.
Methods: All cell lines were obtained from commercial vendors. Drugs were synthesized at Merck KGaA or purchased from commercial vendors. Cell viability upon inhibitor treatment was investigated by Resazurin Cell Viability Assay (R&D Systems), and the effect of the inhibitors on colony forming ability was assessed using colony formation assays. Western blot was conducted to analyze pathway activity. The emergence of resistance was investigated by measuring the cell surface confluence using the IncuCyte S3 system (Essen Bioscience).
Results: The lung cancer cell lines used were NCI-H358 (KRAS G12C), HCC-827 (EGFR L858R), NCI-H2228 (ALK fusion), HCC-78 (ROS1 fusion), and NCI-H1781 (HER2 exon 20 insertion), with their respective targeted therapies sotorasib, osimertinib, alectinib, entrectinib, and poziotinib. The antiproliferative effects of targeted therapies combined with a MET or SHP2 inhibitor were assessed using combination dose matrices in 6-day viability assays. While MET inhibition did not further sensitize the already sensitive cells to the targeted therapies, synergism occurred when the drugs were combined with the SHP2 inhibitor. Similar results were obtained by colony formation assays lasting 2 weeks. Furthermore, the combination of the targeted therapies with the SHP2 inhibitor led to stronger ERK signaling abrogation than with single therapies. In a long-term proliferation assay, the combined inhibition of EGFR and MET receptor delayed the emergence of osimertinib resistance in the EGFR mutant HCC827 cells, which have MET protein overexpression and phosphorylation.
Conclusions: Our data show that combining targeted therapies with a SHP2 inhibitor synergistically decreases the viability of oncogene-driven NSCLC cell lines, indicating that initial combination therapy may be an appealing approach to improve patient outcomes. The observed delay in the emergence of osimertinib resistance, from combining a MET inhibitor with osimertinib, provides preclinical evidence to support further investigating MET inhibition upfront to improve the long-term therapeutic efficacy of EGFR inhibitors.
Citation Format: Nadine Reischmann, Lorenz Pudelko, Christopher Stroh, Nina Linde, Doreen Musch, Marina Keil, Linda Pudelko, Christina Esdar, Andree Blaukat, Karl M. Schumacher, Niki Karachaliou. MET or SHP2 inhibition enhances targeted therapies and delays the emergence of resistance in oncogene-driven NSCLC [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 1105.