Abstract PL01-04: Mechanisms of acquired resistance to ALK/ROS1 inhibitors.

Abstract

Abstract Chromosomal rearrangements of ALK and ROS1 define two distinct molecular subsets of non-small cell lung cancer (NSCLC). The multitargeted tyrosine kinase inhibitor crizotinib is highly active in both ALK- and ROS1-rearranged NSCLC, inducing responses in approximately 60% of patients. However, most patients relapse within the first year or two of treatment due to the development of resistance. Multiple distinct mechanisms of crizotinib resistance have been discovered in resistant tumor specimens and subsequently validated in the laboratory. These include acquisition of secondary resistance mutations in the ALK or ROS1 tyrosine kinase domain, amplification of the target gene, and activation of alternative signaling pathways like EGFR. In this talk, we will review the data supporting these established mechanisms of resistance. In addition, we will describe emerging resistance mechanisms, including epithelial to mesenchymal transition and pharmacokinetic failure leading to both systemic and central nervous system relapses. We will also explore the potential basis for both the homogeneity and heterogeneity of resistance that has been observed in patients. Finally, we will delve into therapeutic strategies that are currently being developed based on our understanding of resistance. These include more potent and selective ALK/ROS1 inhibitors (so called next generation inhibitors), as well as a variety of different combination strategies. These strategies are being tested primarily in patients who have already developed resistance, but they may in fact have greater impact in sensitive, treatment-naive patients by thwarting or delaying the emergence of resistance. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL01-04. Citation Format: Alice T. Shaw. Mechanisms of acquired resistance to ALK/ROS1 inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PL01-04.