New strategies for treatment of ALK-rearranged non-small cell lung cancers

Abstract

The identification of oncogenic alterations in subsets of patients with non-small cell lung cancer (NSCLC) is transforming clinical care. Genomic rearrangements in anaplastic lymphoma kinase (ALK) are detected in 3% to 7% of patients with NSCLC. The ALK tyrosine kinase inhibitor crizotinib has demonstrated clinical efficacy in ALK-rearranged NSCLC patients and was recently approved by the U.S. Food and Drug Administration. Crizotinib is currently under additional phase III clinical development as both initial and second-line therapy for advanced ALK-rearranged NSCLC. However, new challenges in the diagnosis and treatment of this subset of NSCLC have emerged, including the need to determine the most effective means of diagnosing ALK-rearranged NSCLC and the emergence of acquired drug resistance to crizotinib. In this review, we discuss current strategies for treatment and diagnosis, as well as the current knowledge about mechanisms of acquired resistance to crizotinib. Finally, we discuss the strategies that are underway to clinically overcome acquired drug resistance.

Figure 1. ALK signaling in drug sensitive and resistant ALK rearranged cancers

A. Oncogenic ALK activates downstream signaling pathways including the PI3K/Akt, STAT3 and RAS/RAF/ERK signaling pathways. B. Crizotinib inhibits ALK kinase activity leading to inhibition of downstream signaling pathways and resulting in apoptosis. C. ALK secondary mutations (depicted as a black box) prevent crizotinib from inhibiting ALK kinase activity D. EGFR signaling can independently activate downstream signaling pathways even in the presence of ALK inhibition by crizotinib.

Figure 2. Potential therapeutic strategies for critozinib resistant ALK rearranged NSCLC

NSCLC patients that develop acquired resistance can be divided into two major categories based on the presence or absence of an ALK secondary mutation detected in the resistant tumor specimen. For patients with secondary ALK mutations, a different ALK inhibitor, capable of overcoming the resistance mutation, may be an effective treatment strategy. However, if acquired resistance to crizotinib is not mediated by a secondary mutation, combination therapy strategies or HSP90 inhibitors may represent alternative therapeutic approaches.