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Rearrangements in the anaplastic lymphoma kinase (ALK) gene have been detected in ∼3–7% of patients with non-small-cell lung cancer (NSCLC). Crizotinib, an ALK tyrosine kinase inhibitor (TKI), is clinically effective in NSCLC patients with ALK rearrangements. In the phase I clinical trial, a radiographic response rate of 54% was observed. Crizotinib was recently approved by the FDA for the treatment of ALK-positive NSLC. Current clinical trials of crizotinib include two randomized phase III clinical trials. The first compares crizotinib to second-line chemotherapy (either pemetrexed or docetaxel) in ALK-positive NSCLC patients that have failed first-line platinum-based chemotherapy. The second trial compares crizotinib with cisplatin (or carboplatin) and pemetrexed in treatment naïve advanced NSCLC ALK positive patients. In addition to ALK TKIs, inhibitors of heat shock protein (HSP) 90 have demonstrated some clinical activity in EML4-ALK NSCL and are undergoing additional clinical evaluation.

However, despite the impressive clinical efficacy of crizotinib, it is fully anticipated that acquired drug resistance will emerge. Drug resistance mechanisms can in general be divided into two categories: those that result in secondary mutations in the target itself (i.e. ALK) or those that activate parallel signaling pathways. For ALK-positive cancers both mechanisms have been identified to date. Secondary mutations in ALK to date include L1196M, F1174L, C1156Y and L1152R. One example of an alternative signaling pathway that leads to ALK TKI resistance is EGFR. In vitro, some ALK TKI-resistant cell lines have activated EGFR signaling (via EGFR ligands) that promote crizotinib resistance.

The knowledge of a specific drug resistance mechanism is important for choosing the next treatment of ALK positive patients that have developed Crizotinib resistance. In those with evidence of an ALK secondary mutation a more potent ALK inhibitor may be effective. There are several such in preclinical and at least three in phase I clinical development. In cancers harboring activated signaling pathways (such as EGFR) an alternative strategy, a combination of an ALK and EGFR inhibitor, may be effective. A phase I clinical trial is underway combining Crizotinib with the pan-ERBB inhibitor PF299804.

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