Diverse Resistance Mechanisms to the Third-Generation ALK Inhibitor Lorlatinib in ALK-Rearranged Lung Cancer.

Clin Cancer Res 2020 Jan 4;26(1):242-255. Epub 2019 Oct 4.

INSERM 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 kinase domain, other resistance mechanisms driving lorlatinib resistance remain unknown. We aimed to characterize the mechanisms of resistance to lorlatinib occurring in patients with -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 compound mutations. Drug combinatory strategies were evaluated and 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 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 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.

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-1104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942925PMC
January 2020
10 Reads

Publication Analysis

Top Keywords

resistance mechanisms
16
lung cancer
12
compound mutations
12
resistance
9
lorlatinib
9
alk-rearranged lung
8
occurring patients
8
mechanisms resistance
8
resistance lorlatinib
8
alk inhibition
8
lorlatinib resistance
8
therapeutic strategies
8
kinase domain
8
mechanisms
7
alk
5
epithelial-mesenchymal transition
4
overcome lorlatinib
4
evaluated overcome
4
strategies evaluated
4
transition emt
4

Similar Publications