DECIPHERING THE PATHWAYS AT THE BASIS OF RESISTANCE TO CHEMOTHERAPY, IMMUNE-KILLING AND TARGET THERAPY TO IDENTIFY NEW PHARMACOLOGICAL TOOLS AGAINST LUNG CANCER

Non-Small Cell Lung Cancer (NSCLC) is the main cause of cancer-related death in the world. This thesis analyzed the underlying molecular mechanisms of lung cancer chemo-immunoresistance and target therapy resistance, which still represent a challenge in cancer treatment. Evaluation of the expression of Signal Transducer of Activator of Transcription-1 (STAT1) allowed the choice of three NSCLC cell lines, among six different analyzed, to carry out the experiments. The first part of the thesis investigated the role of STAT1 in resistance to chemotherapy and immune-killing: NSCLC cell viability was reduced due to an increase in cancer cells’ chemosensitivity to chemotherapeutics, and an increase in T-lymphocytes proliferation and activation. Moreover, the involvement of paracrine mechanisms in STAT1- dependent therapy resistance was assessed: a differential expression of cytokines was identified, as well as a different proteomic profile in Extracellular Vesicles (EVs) released from wild-type and STAT1-silenced NSCLC cells. Results suggest that STAT1 silencing resensitizes NSCLC cells to cisplatin and paclitaxel-based chemotherapy and immune killing by Tlymphocytes, demonstrating its potential role in mediating resistance through the involvement of paracrine mechanisms. The second part of this work addressed the resistance to epidermal growth factor receptor (EGFR) inhibitors, using erlotinib-sensitive and erlotinib-resistant NSCLC cells. A small library of erlotinib-derivatives containing a ferrocene group was tested, and a panel of top-compounds was identified. These compounds were found to be significantly more effective than erlotinib and independent from classical mechanisms of resistance to EGFR inhibitors. The efficacy of these compounds was due to their ability to release reactive oxygen species (ROS) thanks to the presence of the ferrocene group, resulting in DNA damage, inhibition in G2/M phase of cell cycle, mitochondrial stress and activation of caspase-9 and -3 mediated apoptosis.