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

  • Transl Lung Cancer Res. 2020 Oct;9(5):1810-1821. doi: 10.21037/tlcr-20-681.
Ilaria Attili  1  2  3 ,  Laura Bonanno  4 ,  Niki Karachaliou  1 ,  Jillian Wilhelmina Paulina Bracht  1 ,  Jordi Berenguer  1  5 ,  Carles Codony-Servat  1  6 ,  Jordi Codony-Servat  1 ,  Erika Aldeguer  1 ,  Ana Gimenez-Capitan  1 ,  Alessandro Dal Maso  2  4 ,  Matteo Fassan  7 ,  Imane Chaib  8 ,  Miguel Angel Molina-Vila  1 ,  Antonio Passaro  3 ,  Filippo de Marinis  3 ,  Giulia Pasello  4 ,  Valentina Guarneri  2  4 ,  Pier Franco Conte  2  4 ,  Rafael Rosell  1  9  10  11
Affiliations
  • 1. Pangaea Oncology, Laboratory of Molecular Biology, Coyote Research Group, Quirón-Dexeus University Institute, Barcelona, Spain.
  • 2. Department of Surgery, Oncology and Gastroenterology, Università Degli Studi di Padova, Padova, Italy.
  • 3. Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy.
  • 4. Medical Oncology 2, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.
  • 5. Cancer Stem Cells Metastasis Lab, Hospital del Mar, Medical Research Institute (IMIM), Barcelona Biomedical Research Park (PRBB), Barcelona, Spain.
  • 6. Laboratori de Recerca Translacional-CReST-IDIBELL, Hospitalet de Llobregat, Spain.
  • 7. Surgical Pathology Unit, Department of Medicine (DIMED), Università Degli Studi di Padova, Padova, Italy.
  • 8. Institut d'Investigació en Ciències Germans Trias i Pujol, Badalona, Spain.
  • 9. Instituto Oncologico Dr Rosell (IOR), Quiron-Dexeus University Institute, Barcelona, Spain.
  • 10. Institut d'Investigacio en Ciencies Germans Trias i Pujol, Badalona, Spain.
  • 11. Institut Catala d'Oncologia, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
PMID: 33209603 DOI: 10.21037/tlcr-20-681
Abstract

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.

Keywords
MET; Src; combination treatment; lung cancer; proviral integration site for Moloney murine leukemia virus (PIM).
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