Background
Alectinib is an ALK inhibitor that is currently used for the treatment of ALK-positive NSCLC. This next generation ALK inhibitor was initially used as second-line therapy following resistance to crizotinib. More recently, alectinib has superseded crizotinib, an ALK/ROS1/MET inhibitor, as a first-line therapy due to its superiority in phase III trials. Although patients enjoy durable responses to alectinib, they eventually develop resistance. Here we describe four cases of primary resistance to alectinib in which the patients show little to no response to alectinib when administered as first or second-line therapy.
Method
In order to investigate primary resistance to alectinib, tissue was obtained during re-biopsy and subjected to routine clinical genetic analyses including gene fusion detection and genetic mutation analysis using the Archer FusionPlex and VariantPlex assays, respectively. Concurrently, at the time of biopsy, additional fresh tissue was procured for cell line derivation. The primary cell line was then used to assess ALK and other inhibitors’ potency by cell viability assays. Targeted analysis of signaling pathways was performed in the cell lines via western blot analysis and proximity ligation assays to determine resistance mechanisms.
Result
We present 4 cases of ALK patients with primary resistance to alectinib when used as either first (n=3) or second-line therapy (n=1). In 3 of the 4 cases, routine clinical resistance testing revealed no additional ALK or non-ALK related genetic abnormalities (e.g.; ALK kinase domain mutations, other oncogenic gain-of-function mutations, or gene amplification). However, examination of targeted gene expression data indicated elevated RNA transcripts of MET alone or combined MET and AXL. Analysis of the cell lines derived from these 4 patients further implicates MET in alectinib resistance alone or together with AXL or ERBB3. Signaling analysis shows that MET provides a prosurvival effect, signaling through the PI3K/AKT pathway. In the case where MET was the sole identified bypass mechanism of alectinib resistance, the patient also rapidly progressed through brigatinib, but a regimen of crizotinib plus brigatinib resulted in rapid tumor shrinkage.
Conclusion
Here, we document cases of primary resistance to alectinib therapy using human-derived cell lines to expose novel resistance mechanisms not identified by routine clinical testing. We show that MET is a critical component and serves as a bypass mechanism of alectinib resistance either alone or in combination with AXL or ERBB3. We also demonstrate that crizotinib could overcome MET-mediated ALK resistance in a patient.
Keywords
ALK, MET, alectinib
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© 2019 Published by Elsevier Inc.
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