MOLECULAR INSIGHTS IN ONCOGENE ADDICTED NON SMALL CELL LUNG CANCER

Lung cancer is one of the leading causes of cancer death worldwide and non-small cell lung cancer (NSCLC) represents the most common subgroup. NSCLC includes different histological subtypes: adenocarcinoma (AC), squamous-cell carcinoma (SQCC) and large cell carcinoma (LCC). AC currently, represents the 40-50% of all lung cancers, being the most frequent subtype and is genetically characterized by the accumulation of somatic mutations in the Receptor Tyrosine Kinase (RTK) family of proto-oncogenes. In particular, the most frequent mutated gene is the Epidermal Growth Factor Receptor (EGFR) proto-oncogene. The introduction of molecular therapies against mutant EGFR has greatly improved patient benefits starting from the first- generation Tyrosine Kinase Inhibitors (TKIs) till the recent approval of Osimertinib, a third-generation compound. Notably, the original pre-clinical studies on the use of Osimertinib showed a strong efficacy also for the treatment of EGFR-mutant T790M positive NSCLCs, which were resistant to both first and second generation TKIs. Thus, these promising preclinical studies, rapidly moved the drug to the clinic. Accordingly, the AURA and FLAURA trials clearly demonstrated its superior efficacy in patients as well as its tolerability and safety, thus leading the rapid approval of Osimertinib as a first-line treatment.Notwithstanding, patients, inexorably, relapse and the main resistance mechanisms involve additional mutations on EGFR and the activation of complementary pathways, including also alternative RTKs. The latter involve the amplification of the Mesenchymal-Epithelial Transition (MET) proto-oncogene, a mechanism that was firstly described in Gefitinib resistant clones and currently identified in Osimertinib resistant tumor clones. Preclinical studies on MET amplified resistant cells evidenced the relationship between MET amplification and ERBB3 activation, and the ineffectiveness of monotherapy compared to the stronger combination therapy (anti-EGFR plus anti-MET). The poor efficacy of monotherapy and the great efficacy of combination therapy leaded to the TATTON trial, a phase-1b multi-arm open-label clinical study about the efficacy of the combination treatment of Osimertinib plus Savolitinib.Despite the higher frequency of MET amplification in EGFR-mutant NSCLC, recently this mechanism has been found also in ALK-mutant NSCLC, previously treated with ALK TKIs. Also, in this setting the only effective option to counteract the proliferation of resistant clones, was the combinatorial strategy.Overall these data encourage researchers to the further investigation of combination therapies, in order to assess which is the best treatment in terms of efficacy and safety profile for NSCLC patients to arrest the growth of resistant clones and chronicize the disease.