- Relatively little is known about the contribution of aberrant MET activation to resistance in ALK-positive non-small-cell lung cancer (NSCLC)
- In this study, Massachusetts General Hospital Cancer Center researchers analyzed tumor and/or blood specimens from 136 patients with ALK-positive NSCLC who had relapsed on ALK tyrosine kinase inhibitors
- Genetic alterations of MET were identified in approximately 15% of tumors
- Resistant ALK-positive cell line models and patients with ALK+ lung cancers harboring MET alterations were re-sensitized to treatment with dual ALK/MET inhibition, providing a rationale for the development of novel combinations targeting ALK and MET for ALK-positive NSCLC
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ALK-positive non-small-cell lung cancer (NSCLC) invariably develops resistance even to highly potent, highly selective second-generation ALK tyrosine kinase inhibitors. About half of resistant tumors remain ALK-dependent and respond to treatment with lorlatinib, a third-generation ALK TKI. The rest develop ALK-independent resistance mechanisms, usually due to activation of alternative or bypass signaling pathways.
Preclinical studies have identified MET activation as one of those bypass mechanisms. Now, researchers at the Massachusetts General Hospital Cancer Center have validated MET as a clinically relevant driver of resistance in ALK-positive NSCLC. Alice T. Shaw, MD, PhD, Paula O'Keeffe endowed chair in Thoracic Oncology, Aaron N. Hata, MD, PhD, assistant physician in Hematology and Oncology, Ibiayi Dagogo-Jack, MD, instructor in Thoracic Oncology, researcher Satoshi Yoda, MD, PhD, and colleagues report the findings in Clinical Cancer Research.
Frequency of MET Alterations
The researchers analyzed tumor and/or blood specimens from 136 NSCLC patients who relapsed on ALK TKI therapy. They detected MET amplification and/or MET fusion in about 15% of tumors, including a novel ST7-MET rearrangement in two patients.
ALK/MET Inhibition in Cells
Upregulation of MET signaling through MET amplification and/or ST7-MET fusion decreased sensitivity of ALK-positive cells to ALK inhibitors. In cell lines, combined blockade of ALK and MET overcame resistance driven by MET bypass signaling.
Clinical Activity of ALK/MET Blockade
Two patients with MET-driven resistance to first-line alectinib or ceritinib received crizotinib, which is active against both ALK and MET (it was combined with lorlatinib in patient 2). Both patients showed rapid clinical and radiographic responses but relapsed after approximately three months. Biopsies showed persistent MET amplification in both cases, and patient 1 had multiple ALK resistance mutations that were not detected before crizotinib therapy.
Future studies should identify molecular determinants of resistance to combined ALK/MET inhibition, explore whether line of therapy affects response and assess the efficacy of more potent MET TKIs, such as capmatinib and savolitinib.
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