MET addicted tumors are known to show very short response to single MET inhibition. In MET addicted cells, MET inhibition leads to activation of proviral integration site for Moloney murine leukemia virus-1 (PIM1). PIM1 and SRC can regulate the expression of receptor tyrosine kinases (RTKs), potentially being responsible of resistance to MET inhibition. We previously showed that the dual inhibition of MET and PIM1 with class I MET inhibitors and the pan-PIM inhibitor AZD1208, as well as MET and SRC (with dasatinib), is synergistic in MET addicted cell lines.
We evaluated the activity of class I and class II MET inhibitors, MET/SRC/CSF1R inhibitor TPX-02226 and pan-PIM inhibitors AZD1208 and PIM447 in four MET addicted cell lines: 2 MET amplified lung cancer cell lines (EBC1 and H1993), 1 MET exon 14 mutant cell line (Hs746T) and 1 MET exon 7-8 splicing variant cell line (E98). We assessed the effect of the dual inhibition of MET and PIM, and the triple inhibition of MET, SRC and PIM in cell viability by combining the TPX-02226 with the pan-PIM inhibitors.
All cell lines were sensitive to class I-II MET inhibitors (IC50s in nM range) except for cabozantinib in H1993. Only the MET amplified cell lines were sensitive to TPX-02226. All cell lines were resistant to PIM inhibition. The combination of class I MET inhibitors with PIM447 showed stronger synergism in the MET amplified cell lines, compared to the combination with AZD1208. Class I-II MET inhibitors and PIM inhibitor combination showed only additive effect in exon 7-8 cell line E98, while the combination of TPX-02226 and PIM447 was strongly synergistic.
We identified potential role of PIM inhibition in MET amplified tumors. Even though single agent TPX-02226, AZD1208 or PIM447 showed no activity and dual MET/PIM inhibition showed only additive effect, the triple inhibition of MET, SRC and PIM was strongly effective in MET exon 7-8 splicing variant, suggesting a crucial role of SRC-PIM interaction in this still not well recognized MET addicted tumor. Further investigation on this triple inhibition is ongoing in MET addicted cell lines and role of co-presence of MET and PIM1 and/or SRC alterations in tumor samples.
Clinical trial identification
Legal entity responsible for the study
IGTP, Germans Trias i Pujol Research Institute, Badalona, Barcelona, Spain.
Fundació Obra Social “La Caixa”.
J.J. Cui: Leadership role, Officer / Board of Directors: TP Therapeutics. N. Karachaliou: Officer / Board of Directors: Merck KgaA. All other authors have declared no conflicts of interest.