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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
Transformation from adenocarcinoma to squamous cell lung carcinoma with MET amplification after lorlatinib
Shoko Ueda1, Takehito Shukuya1, Takuo Hayashi2
1Department of Respiratory Medicine' Juntendo University, Tokyo, Japan.
Abstract:
To date, several studies have described the mechanism of resistance to first- or second-generation anaplastic lymphoma kinase (ALK) inhibitors. Secondary ALK mutations, ALK gene amplification, and other bypass signal activations (i.e., KRAS mutation, EGFR mutation, amplification of KIT, and increased autophosphorylation of EGFR) are known as resistance mechanisms. However, little has been previously reported on acquired resistance mechanisms to lorlatinib. Here, we report a case of a patient with ALK-positive lung adenocarcinoma that acquired resistance to lorlatinib during treatment for brain metastasis and showed histological transformation to squamous cell carcinoma with MET amplification. We also review the previous literature on the resistance mechanism to ALK inhibitors.
Insights
Resistance to lorlatinib, an anaplastic lymphoma kinase (ALK) inhibitor, can occur through histological transformation to squamous cell carcinoma with MET amplification. This case highlights a novel resistance mechanism in ALK-positive lung cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Anaplastic lymphoma kinase (ALK) inhibitors are crucial in treating ALK-positive non-small cell lung cancer.
- Established resistance mechanisms include secondary ALK mutations, gene amplification, and bypass signaling pathway activation.
- Lorlatinib represents a third-generation ALK inhibitor with a distinct resistance profile.
Observation:
- A patient with ALK-positive lung adenocarcinoma developed resistance to lorlatinib during treatment for brain metastases.
- Histological examination revealed a transformation to squamous cell carcinoma.
- This transformation was associated with MET gene amplification.
Findings:
- This case presents a novel mechanism of acquired resistance to lorlatinib.
- MET amplification in the context of histological transformation to squamous cell carcinoma is identified as a potential resistance pathway.
- This contrasts with previously documented resistance mechanisms primarily involving ALK alterations or other bypass pathways.
Implications:
- Understanding acquired resistance mechanisms is vital for optimizing treatment strategies in ALK-positive lung cancer.
- The identification of MET amplification and histological transformation suggests potential therapeutic targets for overcoming lorlatinib resistance.
- Further research is warranted to validate these findings and explore combination therapies.
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