Treating ALK-positive lung cancer—early successes and future challenges

Abstract

Rearrangements of the anaplastic lymphoma kinase (ALK) gene occur infrequently in non-small cell lung cancer (NSCLC), but provide an important paradigm for oncogene-directed therapy in this disease. Crizotinib, an orally bioavailable inhibitor of ALK, provides significant benefit for patients with ALK positive (ALK+) NSCLC in association with characteristic, mostly mild, toxicities and is now FDA approved in this molecularly defined subgroup of lung cancer. Many new ALK inhibitors are being developed and understanding the challenges of determining and addressing the side-effects that are likely to be ALK specific, maximizing the time of benefit on targeted agents, and understanding the mechanisms that underlie drug resistance will be critical in informing the optimal therapy of ALK+NSCLC in the future.

First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer

“…1,2 They define a distinct subgroup of NSCLC that typically occurs in younger patients who have never smoked or have a history of light smoking and that has adenocarcinoma histologic characteristics. [3][4][5] Crizotinib is an oral small-molecule tyrosine kinase inhibitor of ALK, MET, and ROS1 kinases. 6 In phase 1 and 2 studies, crizotinib treatment resulted in objective tumor responses in approximately 60% of patients with ALK-positive NSCLC and in progression-free survival of 7 to 10 months.…”

The R1275Q Neuroblastoma Mutant and Certain ATP-competitive Inhibitors Stabilize Alternative Activation Loop Conformations of Anaplastic Lymphoma Kinase

“…In cellular assays, it is generally accepted that the F1174L mutant displays reduced sensitivity to crizotinib relative to the R1275Q mutant or to wild-type enzyme, although the reported level of reduced sensitivity varies (33,35,36,54). In the clinical setting, recent reports also identify the F1174L variant and the related F1174C variant as secondary mutations conferring resistance to crizotinib therapy in patients harboring an oncogenic ALK fusion protein (36,37). The reduced sensitivity of F1174L ALK to crizotinib is reported to be due, at least in part, to a reduced K m,ATP and an increased catalytic efficiency in this mutant (35).…”

“…As with the ALK fusion proteins, the neuroblastoma activating mutants are amenable to inhibition by small molecule inhibitors of the ALK kinase activity, although differential sensitivity has been observed depending on the particular inhibitor and mutant (33,35). Interestingly, the F1174L variant and the related F1174C variant have been independently identified in the clinic as a mutations conferring resistance to crizotinib treatment (36,37).…”

Lactate Dehydrogenase B Is Required for the Growth of KRAS-Dependent Lung Adenocarcinomas

“…Oncogenic alterations in the kinases EGF receptor (EGFR) and anaplastic lymphoma kinase (ALK) are found in 15% to 25% of NSCLC (3,4). Patients with tumors harboring the activated EGFR and ALK kinase respond to the tyrosine kinase inhibitors gefitinib and erlotinib (5,6) and crizotinib (7), respectively.…”