Lorlatinib and capmatinib in a ROS1-rearranged NSCLC with MET-driven resistance: tumor response and evolution.
Jaime L SchneiderKhvaramze ShaverdashviliMari A Mino-KenudsonSubba R DigumarthyAndrew DoAudrey LiuJustin F GainorJochen K LennerzTimothy F BurnsJessica J LinPublished in: NPJ precision oncology (2023)
Acquired drug resistance remains a major problem across oncogene-addicted cancers. Elucidation of mechanisms of resistance can inform rational treatment strategies for patients relapsing on targeted therapies while offering insights into tumor evolution. Here, we report acquired MET amplification as a resistance driver in a ROS1-rearranged lung adenocarcinoma after sequential treatment with ROS1 inhibitors. Subsequent combination therapy with lorlatinib plus capmatinib, a MET-selective inhibitor, induced intracranial and extracranial tumor response. At relapse, sequencing of the resistant tumor revealed a MET D1246N mutation and loss of MET amplification. We performed integrated molecular analyses of serial tumor and plasma samples, unveiling dynamic alterations in the ROS1 fusion driver and MET bypass axis at genomic and protein levels and the emergence of polyclonal resistance. This case illustrates the complexity of longitudinal tumor evolution with sequential targeted therapies, highlighting challenges embedded in the current precision oncology paradigm and the importance of developing approaches that prevent resistance.
Keyphrases
- tyrosine kinase
- combination therapy
- cell death
- dna damage
- reactive oxygen species
- end stage renal disease
- single cell
- rheumatoid arthritis
- dna methylation
- palliative care
- endothelial cells
- prognostic factors
- small molecule
- newly diagnosed
- disease activity
- peritoneal dialysis
- oxidative stress
- systemic lupus erythematosus
- nucleic acid
- protein protein
- binding protein