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27/07/2017

Unmasking the molecular mechanisms driving resistance to targeted therapy against metastatic non-small cell lung cancer

Published as an open access article last week in the flagship journal of the European Society of Medical Oncology (ESMO), Annals of Oncology, latest research reported by VHIO investigators and physician-scientists have identified a novel and more effective therapeutic strategy aimed at combatting acquired resistance to third generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs), osimertinib, in the treatment of metastatic non-small cell lung cancer (NSCLC) EGFR-mutant harboring T790M.

As a purely multidisciplinary and translational VHIO tour de force combining the expertise of Enriqueta Felip, Principal Investigator of VHIO´s Thoracic Tumors & Head and Neck Cancer Group with co-first author Alex Martínez, Medical Oncologist and Clinical Investigator of her group, along with other members of her team and the essential efforts of Ana Vivancos, Principal Investigator of Cancer of VHIO´s Cancer Genomics Group and Co-Corresponding Author, these findings have significantly advanced insights into the molecular mechanisms that govern progression to successive EFGR TKIs lines in EGFR-mutant lung cancer.

Using a patient-derived orthotopic xenograft model (PDOX), they have successfully characterized the role of MET gene amplification and signaling as a mechanism of resistance to osimertinib, and evidenced the superior efficacy of pairing EGFR inhibitor afatinib with c-MET inhibitor, capmatinib.

“Considering that around 85% of lung cancers are non-small cell lung cancer and that these tumors are notoriously resistant to current targeted therapies and therefore progress, we must continue to center our efforts on identifying more powerful and personalized strategies to overcome successive acquired mechanisms of resistance”, observes Alex Martínez.

“In order to provide fresh hope for these patients, we need to raise the bar even higher in our collective efforts aimed at reversing cancer drug resistance. We will therefore continue to focus on exploring the EGFR-TKI-MET inhibitor combination as a novel therapeutic strategy as well as consider the addition of immunotherapy for the potential treatment of these patients at earlier stages”
, he concludes.

To view and download this paper*, now published open access and online in Annals of Oncology, please click here.

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*A. Martinez-Marti, E. Felip, J. Matito, E. Mereu, A. Navarro, S. Cedrés, N. Pardo, A. Martinez de Castro, J. Remon, JM. Miquel, A. Guillaumet-Adkins, E. Nadal, G. Rodriguez-Esteban, O. Arqués, R. Fasani, P. Nuciforo, H. Heyn, A. Villanueva, H. G. Palmer, A. Vivancos; Dual MET and ERBBinhibition overcomes intra-tumor plasticity in osimertinib resistant advanced non-small cell lung cancer (NSCLC). Ann Oncol 2017 mdx396. doi: 10.1093/annonc/mdx396.
 

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