ALK inhibitors in non-small cell lung cancer: the latest evidence and developments

Abstract

Abstract:The treatment of patients with advanced non-small cell lung cancer (NSCLC) harbouring chromosomal rearrangements of ALK (anaplastic lymphoma kinase) was revolutionized by crizotinib, a small molecule inhibitor of ALK, ROS1 and MET. Unfortunately, the disease progressed within the first 12 months in most of the patients because of the development of crizotinib resistance in the majority of patients and the emergence of acquired resistance mutations in most of them. Many of them had been reported even before its approval leading to the rapid development of second-generation ALK inhibitors for crizotinibresistant NSCLC. In the last few years, novel potent ALK inhibitors with promising results and a good toxicity profile have become available: ceritinib (LDK378), alectinib (RG7853/ AF-802/RO5424802/CH5424802), brigatinib (AP26113), entrectinib (RXDX-101, NMS-E628), PF-06463922, ASP3026, TSR-011, X-376/X-396 and CEP-28122/CEP-37440. Moreover, HSP90 (90 kDa heat shock protein) inhibitors have demonstrated clinical activity in patients with ALK+ NSCLC. This review focuses on the molecular and clinical properties of this new generation of ALK inhibitors under development in the clinic.

Fisetin inhibits the growth and migration in the A549 human lung cancer cell line via the ERK1/2 pathway

“…Lung cancer is classified into two major types: Small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Most lung cancers are NSCLCs, which account for nearly 90% of cases (2). At present, surgical resection and chemotherapy are the major means of treating NSCLC.…”

“…Lung cancer is the most common tumor type in the developed world and in 2012 it was the most commonly diagnosed cancer (1.82 million) and the most common cause of cancer mortality (1.6 million) worldwide (1,2). Lung cancer is classified into two major types: Small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).…”

Integrin β3 Inhibition Enhances the Antitumor Activity of ALK Inhibitor in ALK-Rearranged NSCLC

“…Because of their benefits over other therapies, ALK tyrosine kinase inhibitors (ALK TKIs) are used as the chemotherapeutic agents of choice in NSCLC with ALK rearrangement (6). However, most cases receiving ALK inhibitors relapse within a few years after starting therapy (7)(8)(9)(10). Ongoing research mainly attempts to develop new small molecule inhibitors with greater potency against ALK and activity against acquired mutations (11).…”

Precision medicine in lung cancer: the battle continues

“…ALK kinase domain mutations, including L1196M, C1156Y and G1202R among others, have been observed in approximately a third of patients (16). The activity of next generation ALK inhibitors such ceritinib and alectinib may depend on the secondary ALK mutations.…”