Abstract
<div>AbstractPurpose:<p>Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor with proven efficacy in patients with ALK-rearranged lung cancer previously treated with first- and second-generation ALK inhibitors. Beside compound mutations in the <i>ALK</i> kinase domain, other resistance mechanisms driving lorlatinib resistance remain unknown. We aimed to characterize the mechanisms of resistance to lorlatinib occurring in patients with <i>ALK</i>-rearranged lung cancer and design new therapeutic strategies in this setting.</p>Experimental Design:<p>Resistance mechanisms were investigated in 5 patients resistant to lorlatinib. Longitudinal tumor biopsies were studied using high-throughput next-generation sequencing. Patient-derived models were developed to characterize the acquired resistance mechanisms, and Ba/F3 cell mutants were generated to study the effect of novel <i>ALK</i> compound mutations. Drug combinatory strategies were evaluated <i>in vitro</i> and <i>in vivo</i> to overcome lorlatinib resistance.</p>Results:<p>Diverse biological mechanisms leading to lorlatinib resistance were identified. Epithelial–mesenchymal transition (EMT) mediated resistance in two patient-derived cell lines and was susceptible to dual SRC and ALK inhibition. We characterized three <i>ALK</i> kinase domain compound mutations occurring in patients, L1196M/D1203N, F1174L/G1202R, and C1156Y/G1269A, with differential susceptibility to ALK inhibition by lorlatinib. We identified a novel bypass mechanism of resistance caused by <i>NF2</i> loss-of-function mutations, conferring sensitivity to treatment with mTOR inhibitors.</p>Conclusions:<p>This study shows that mechanisms of resistance to lorlatinib are diverse and complex, requiring new therapeutic strategies to tailor treatment upon disease progression.</p></div>
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