Combined use of tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) as target therapy in non-small cell lung cancer (NSCLC)

Abstract

Two main strategies targeting ErbB receptors have been developed: small-tyrosin kinase inhibitors (TKIs) such as gefitinib and erlotinib, and monoclonal antibodies (mAbs) such as cetuximab and trastuzumab. In NSCLC patients, many molecular aberration have been identified including EGFR, BRAF, HER2 amplification/mutations, EML4-ALK, ROS and RET rearrangements in adenocarcinoma, FGFR amplification/mutations, DDR2 or PI3KCA mutation in squamous cell carcinoma. All of these aberrations have been correlated with a poor prognosis. Erlotinib is an effective treatment for NSCLC patients and has been registered as a second and third-line treatment of NSCLC regardless of EGFR mutation status. Gefitinib has been registered for the therapy of advanced NSCLC harbouring activating EGFR mutations in the tyrosine kinase domain, the most frequent being L858R in exon 21 and Del (746–750) in exon 19. Although mutations in EGFR are useful predictors for the activity of EGFR-TKI, they cannot be used as the only criterion to determine who should receive anti-EGFR therapy and it is becoming increasingly clear that even patients with EGFR wild-type can benefit from EGFR-TKI. Cetuximab is a chimeric IgG1 monoclonal antibody (mAb) that blocks ligand binding to EGFR, leading to a decrease in receptor dimerization, autophosphorylation, and activation of signaling pathways. In addition the binding of cetuximab initiates EGFR internalization and degradation which leads to signal termination. Moreover, unlike EGFR-TKIs, cetuximab can induce antibody dependent cellular cytotoxicity (ADCC) activity, an important immunologic antitumour effect. Cetuximab in combination with chemotherapy has been approved by the FDA for the treatment of metastatic colorectal cancer and of locally advanced head and neck cancer. Trastuzumab, registered for the treatment of HER2 positive breast cancer, has also been tested in phase II trials as a single agent and in combination with cytotoxic chemotherapy for patients with NSCLC. The acquisition of resistance to tyrosine kinase inhibitors (TKIs) in clinical oncology is a well documented phenomenon that applies to several types of cancers. Almost all NSCLC patients with activating EGFR mutations treated with EGFR-TKI, after an initial response, experience disease progression within 10 to 14 months from the beginning of the therapy. A commonly described mechanism of drug resistance involves additional genetic alterations within the EGFR itself, the most frequent being the T790M mutation accounting for approximately 50% of cases of acquired resistance. The potential clinical relevance of HER2 expression in NSCLC is currently under evaluation, however, the recent role of HER2 amplification in the acquisition of resistance to TKI, reported in 12-13% of patients, may render HER2 a potential target not only in breast cancer but also in NSCLC. T-DM1, trastuzumab emtansine, is an antibody-drug conjugate composed by the microtubule polymerization inhibitor DM1 (derivative of maytansine) linked with a stable thioether linker to trastuzumab. Several preclinical studies on cell lines from different tumour types, indicated that the association between EGFR/HER2 mAbs with TKIs displays an increased efficacy. The aim of my thesis was to explore the potential of combining erlotinib with either cetuximab or trastuzumab in order to improve the efficacy of EGFR targeted therapy in EGFR wild-type sensitive NSCLC cell lines. Because HER2 represents a relatively new therapeutic target for NSCLC, I evaluated whether T-DM1 activity is affected by HER2 expression/mutation status and may overcame EGFR-TKI resistance in NSCLC cell lines.