Genetic, epigenetic and micro-environmental markers as predictors of prognosis, response and resistance to chemotherapy, targeted agents and immunotherapy in resected squamous cell lung carcinoma (SQLC).

Differently from lung adenocarcinoma, effective targeted therapies for lung squamous-cell cancer (SQLC) are still missing, although a series of molecular pathways are constantly altered. In this regard, the prognostic and/or predictive impact of potential drivers needs to be elucidated, in order to create a global portrait of SQLC patients. Nowadays, one of the main emerging research strategies in cancer is centered on the study of the genome of exceptional responder and prognostic outlier patients. Adopting this idea, we retrospectively analysed a multicenter series of 573 surgically resected SQLC patients and we built one of the first risk classification model for SQLC, which was afterwards validated in a larger cohort of more than 1000 patients. This model, based on a combination of simple and easily available clinicopathological parameters, was able to effectively stratify resected SQLC patients in risk classes with a good prognostic accuracy. Once identified the best and worst prognostic performers, we investigated their molecular portrait, principally by next-generation sequencing (NGS), and their expression profile to identify recurrent molecular alterations and explore their association with prognosis. Sixty and forty-seven patients were evaluated as training and validation cohort, respectively. Copy number variation (CNV) was the most frequent genomic event. Molecular alterations were distributed regardless of prognosis, except from DDR2 mutations in good prognosis group and SMAD4 loss in poor prognosis group. The potentially druggable PI3KCA/mTOR axis represented the most frequently altered pathway (42%), with PI3KCA mutations and RICTOR high gain reported only in poor prognosis group. Upon transcriptome analysis, RICTOR high gain patients presented an increased pathway activity. The final aim of the overall project was to evaluate the molecular profile of outliers resected SQLC taking the advantage to adopt modern technologies in order to identify those molecular aberrations potentially able to predict the probability of disease recurrence and the efficacy of agents selectively targeting these candidate pathways. This integrated multi-step analysis performed in almost one hundred resected SQLC patients identified altered pathways with a biological impact in SQLC oncogenesis, revealing RICTOR high gain as a candidate therapeutical target for selective inhibition in SQLC.