New Molecular Targets in the Treatment of NSCLC

Clorinda      Schettino; Maria   Anna   Bareschino; Paola   Claudia   Sacco; Paolo      Maione; Antonio      Rossi; Francesca      Casaluce; Assunta      Sgambato; Cesare      Gridelli

Abstract

Lung cancer is the leading cause of mortality world-wide. Non Small Cell Lung Cancer (NSCLC) is a particularly aggressive cancer, the optimum management of which is still being determined. In the next years modest survival improvement can be expected by chemotherapy. Advances in understanding of the molecular pathogenesis of lung cancer have led to the identification of several specific targets for therapeutic agents.

Targeting the epidermal growth factor receptor (EGFR) has played a central role in advancing NSCLC research, treatment, and patient outcome over the last several years.

In lung cancer, 10-15% of NSCLC contain activating mutations in the EGFR kinase conferring hypersensitivity to the oral TKIs gefitinib and erlotinib, have been demonstrated to be important predictive factors when selecting patients to be treated with these two agents.

More recently, another molecular abnormality, the translocation of the anaplastic lymphoma kinase (ALK) gene that drives NSCLC in a different group of patients has been found in 4 to 5% of NSCLC. The rearrangement results in an EML4 – AKL fusion gene, which increases ALK activity. Inhibitors of ALK kinase have been developed and investigated.

Crizotinib, an orally ALK and met proto-oncogene (MET) inhibitor, was very well tolerated and produced dramatic antitumor activity in early-stage trials which facilitated a faster than normal move into late-stage trials for EML4-ALK –positive NSCLC patients treatment. In a phase III randomized that showed progression free survival benefit as compared to chemotherapy in second-line setting.

Several novel selective inhibitors of ALK kinase are currently in preclinical or early clinical testing. Since the discovery that Met pathway is one of the most frequently dysregulated pathways in human cancer, Met inhibitors, with varying kinase selectivity profiles ranging from highly selective to multi-targeted have been studied in the clinic and good progress has been achieved.

A number of studies suggest that the PI3K/Akt signaling pathway is central to NSCLC growth and survival. Given the importance of activated PI3K signaling in cancer, several PI3K inhibitors are currently one of the most recent drug targets in oncology, with several small molecules in early stages of clinical development.

This review will focus on the role of EGFR, ALK, MET, and PI3K inhibitors in the treatment of NSCLC.

Keywords: NSCLC, EGFR, gefitinib, erlotinib, ALK, crizotinib, c-MET, PI3K.