Diverse Resistance Mechanisms to the Third-Generation ALK Inhibitor Lorlatinib in ALK-Rearranged Lung Cancer
Gonzalo Recondo1,2, Laura Mezquita3, Francesco Facchinetti1,2
1INSERM U981, Gustave Roussy Cancer Campus, Villejuif, France.
Purpose:
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 ALK kinase domain, other resistance mechanisms driving lorlatinib resistance remain unknown. We aimed to characterize the mechanisms of resistance to lorlatinib occurring in patients with ALK-rearranged lung cancer and design new therapeutic strategies in this setting.
Experimental Design:
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 ALK compound mutations. Drug combinatory strategies were evaluated in vitro and in vivo to overcome lorlatinib resistance.
Results:
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 ALK 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 NF2 loss-of-function mutations, conferring sensitivity to treatment with mTOR inhibitors.
Conclusions:
This study shows that mechanisms of resistance to lorlatinib are diverse and complex, requiring new therapeutic strategies to tailor treatment upon disease progression.
Insights
Resistance to lorlatinib in ALK-rearranged lung cancer is complex, involving diverse mechanisms like EMT and novel ALK mutations. New therapeutic strategies are needed to overcome lorlatinib resistance.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK) inhibitor for ALK-rearranged lung cancer.
- Mechanisms of lorlatinib resistance beyond ALK mutations are largely unknown.
- Understanding resistance is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To characterize resistance mechanisms to lorlatinib in patients with ALK-rearranged lung cancer.
- To identify novel therapeutic strategies to overcome lorlatinib resistance.
Main Methods:
- Analysis of longitudinal tumor biopsies from 5 lorlatinib-resistant patients using next-generation sequencing.
- Development of patient-derived models and Ba/F3 cell mutants to study resistance.
- Evaluation of drug combination strategies in vitro and in vivo.
Main Results:
- Identified diverse resistance mechanisms including epithelial-mesenchymal transition (EMT) and novel ALK compound mutations (L1196M/D1203N, F1174L/G1202R, C1156Y/G1269A).
- Discovered NF2 loss-of-function mutations as a novel resistance mechanism conferring sensitivity to mTOR inhibitors.
- Demonstrated that EMT-mediated resistance is susceptible to dual SRC and ALK inhibition.
Conclusions:
- Resistance to lorlatinib is multifaceted, necessitating tailored treatment approaches.
- Novel therapeutic strategies targeting EMT, specific ALK mutations, or bypass pathways like NF2 are required.
- Personalized treatment strategies are essential for managing lorlatinib resistance in ALK-rearranged lung cancer.
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