SRC and PIM1 as potential co-targets to overcome resistance in MET deregulated non-small cell lung cancer.

BACKGROUND

The role of MET alterations in non-small cell lung cancer (NSCLC) is increasing and several targeted agents are under evaluation. MET exon 14 skipping mutations and MET amplifications are associated with potential sensitivity to MET inhibition, though resistance mechanisms are emerging. In MET addicted cells, MET inhibition leads to activation of proviral integration site for Moloney murine leukemia virus-1 (PIM1). PIM1 and proto-oncogene tyrosine-protein kinase Src (SRC) can regulate the expression of receptor tyrosine kinases (RTKs), potentially inducing resistance to MET inhibition through cross-activation.

METHODS

We evaluated the activity of class I-II MET inhibitors, the SRC inhibitor dasatinib, and pan-PIM inhibitors in four MET addicted cell lines. We assessed the effect of the dual MET/PIM and MET/SRC inhibition on cell viability and at the protein level. We evaluated RNA expression profiles of the cell lines. Advanced NSCLCs were also screened for MET alterations.

RESULTS

All cell lines were sensitive to class I-II MET inhibitors. All cell lines were resistant to single PIM and SRC inhibition. Dual MET/PIM inhibition was synergistic or additive in MET amplified cell lines and dual MET/SRC inhibition was highly synergistic in all MET addicted cell lines. The addition of an SRC inhibitor partially prevents the RTKs cross-activation. MET alterations were found in 9 out of 97 evaluable samples (9.3%); median overall survival in MET altered patients was 5 months (95% CI, 3 m-NA).

CONCLUSIONS

We identified a potential role of PIM inhibition in MET amplified tumors and of SRC inhibition in MET addicted tumors. Potential applications of this new treatment strategy warrant further evaluation.

Informations de copyright

2020 Translational Lung Cancer Research. All rights reserved.

Déclaration de conflit d'intérêts

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-20-681). NK and RR serve as unpaid editorial board members of Translational Lung Cancer Research. AP reports personal fees AstraZeneca, Roche, Eli Lilly, BMS, MSD, Dako/Agilent, Pfizer, outside the submitted work. FM reports personal fees from AstraZeneca, Roche, Novartis, BMS, MSD, Takeda, Pfizer outside the submitted work. GP reports personal fees from Astrazeneca, BMS, Boehringer Ing, MSD, Roche, Eli Lilly & Co., outside the submitted work. VG reports personal fees from Astrazeneca, Novartis, Roche, Eli Lilly & Co., outside the submitted work. The authors have no other conflicts of interest to declare.