TY - JOUR
T1 - SRC and PIM1 as potential co-targets to overcome resistance in MET deregulated non-small cell lung cancer
AU - Attili, Ilaria
AU - Bonanno, Laura
AU - Karachaliou, Niki
AU - Bracht, Jillian Wilhelmina Paulina
AU - Berenguer, Jordi
AU - Codony-Servat, Carles
AU - Codony-Servat, Jordi
AU - Aldeguer, Erika
AU - Gimenez-Capitan, Ana
AU - Maso, Alessandro Dal
AU - Fassan, Matteo
AU - Chaib, Imane
AU - Molina-Vila, Miguel Angel
AU - Passaro, Antonio
AU - de Marinis, Filippo
AU - Pasello, Giulia
AU - Guarneri, Valentina
AU - Conte, Pier Franco
AU - Rosell, Rafael
N1 - Funding Information:
This work was supported by La Caixa. Funding: None.
Publisher Copyright:
© Translational Lung Cancer Research. All rights reserved.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/10
Y1 - 2020/10
N2 - 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.
AB - 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.
KW - Combination treatment
KW - Lung cancer
KW - MET
KW - Proviral integration site for Moloney murine leukemia virus (PIM)
KW - Src
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U2 - 10.21037/tlcr-20-681
DO - 10.21037/tlcr-20-681
M3 - Article
AN - SCOPUS:85096141884
VL - 9
SP - 1810
EP - 1821
JO - Translational Lung Cancer Research
JF - Translational Lung Cancer Research
SN - 2226-4477
IS - 5
ER -