SHP2 Inhibition Influences Therapeutic Response to Tepotinib in Tumors with MET Alterations

Linda Pudelko; Frank Jaehrling; Christof Reusch; Sanziago Vitri; Christopher Stroh; Nina Linde; Michael P Sanderson; Doreen Musch; Catherine Jorand Lebrun; Marina Keil; Christina Esdar; Andree Blaukat; Rafael Rosell; Karl Maria Schumacher; Niki Karachaliou

doi:10.1016/j.isci.2020.101832

SHP2 Inhibition Influences Therapeutic Response to Tepotinib in Tumors with MET Alterations

iScience. 2020 Nov 20;23(12):101832. doi: 10.1016/j.isci.2020.101832. eCollection 2020 Dec 18.

Authors

Linda Pudelko¹, Frank Jaehrling¹, Christof Reusch¹, Sanziago Vitri², Christopher Stroh¹, Nina Linde¹, Michael P Sanderson¹, Doreen Musch¹, Catherine Jorand Lebrun³, Marina Keil¹, Christina Esdar¹, Andree Blaukat¹, Rafael Rosell^{2

4

5

6}, Karl Maria Schumacher⁷, Niki Karachaliou^{1

7}

Affiliations

¹ Translational Innovation Platform Oncology, Merck KGaA, Darmstadt 64293, Germany.
² Rosell Oncology Institute (IOR), Dexeus University Hospital, QuironSalud Group, 08028 Barcelona, Spain.
³ Medicinal Chemistry, EMD Serono, Billerica, MA 01821, USA.
⁴ Germans Trias i Pujol Research Institute and Hospital (IGTP), Molecular and Cellular Oncology Laboratory, Badalona 08916, Spain.
⁵ Pangaea Oncology, Laboratory of Molecular Biology, Quirón-Dexeus University Institute, 08028 Barcelona, Spain.
⁶ Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona 08916, Spain.
⁷ Global Clinical Development, Merck KGaA, Darmstadt 64293, Germany.

Abstract

Tepotinib is an oral MET inhibitor approved for metastatic non-small cell lung cancer (NSCLC) harboring MET exon 14 (METex14) skipping mutations. Examining treatment-naive or tepotinib-resistant cells with MET amplification or METex14 skipping mutations identifies other receptor tyrosine kinases (RTKs) that co-exist in cells prior to tepotinib exposure and become more prominent upon tepotinib resistance. In a small cohort of patients with lung cancer with MET genetic alterations treated with tepotinib, gene copy number gains of other RTKs were found at baseline and affected treatment outcome. An Src homology 2 domain-containing phosphatase 2 (SHP2) inhibitor delayed the emergence of tepotinib resistance and synergized with tepotinib in treatment-naive and tepotinib-resistant cells as well as in xenograft models. Alternative signaling pathways potentially diminish the effect of tepotinib monotherapy, and the combination of tepotinib with an SHP2 inhibitor enables the control of tumor growth in cells with MET genetic alterations.

Keywords: Cancer; Treatment.