Title:Resistance to Crizotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) with ALK Rearrangement: Mechanisms, Treatment Strategies and New Targeted Therapies
Volume: 11
Issue: 2
Author(s): Francesca Casaluce, Assunta Sgambato, Paola Claudia Sacco, Giovanni Palazzolo, Paolo Maione, Antonio Rossi, Fortunato Ciardiello and Cesare Gridelli
Affiliation:
Keywords:
Acquired resistance, anaplastic lymphoma kinase, ceritinib, crizotinib, heat shock protein 90, non–small cell lung
cancers, targeted therapy.
Abstract: Non–small cell lung cancers (NSCLCs) harboring anaplastic lymphoma kinase (ALK)
rearrangement are generally responsive to treatment with ALK tyrosine kinase
inhibitors (TKIs). Crizotinib is the first-in-class TKI approved as front-line or salvage
therapy in advanced ALK-rearranged NSCLC. Unfortunately, drug resistance
develops after initial benefit, through a variety of mechanisms preserving or not the
dominance of ALK signaling in the crizotinib-resistant state. The distinction between
patients who preserve ALK dominance (secondary mutations alone or in combination
with the number of copy ALK gain) compared to those that have decreased ALK
dominance (separate or second oncogenic drivers, with or without concurrent
persistence of the original ALK signal) is important in order to overcome resistance.
Novel second-generation ALK inhibitors are currently in clinical development with
promising results in ALK-rearranged NSCLC, as well as in crizotinib-resistant patients. Among these,
ceritinib in the United States was granted by Food and Drug Administration accelerated approval for
treatment of patients with ALK-rearranged, metastatic NSCLC with progression disease on or intolerance
to crizotinib. Fully understanding of the different mechanisms of resistance to crizotinib will help us to
continue to exploit personalized medicine approaches overcoming crizotinib resistance in these patients in
the future. This review aims to discuss on strategy overcoming crizotinib-resistance starting from
molecular mechanisms of resistance until novel ALK kinase inhibitors in ALK-rearranged NSCLC
patients.
