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Potential Therapeutic Strategy for EGFR-Mutant Lung Cancer With Concomitant EML4-ALK Rearrangement-Combination of
Ming-Hung Huang1, Jih-Hsiang Lee1,2, Pei-Shan Hung1
1Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Introduction:
Although driver gene mutations have been believed to be mutually exclusive, some patients with NSCLC and concomitant EGFR mutations and EML4-ALK rearrangements have been reported. In this study, we reported a case of a patient with lung cancer who harbored both EGFR mutation and the EML4-ALK rearrangement after acquiring resistance to the EGFR tyrosine kinase inhibitor treatment. EGFR-mutant and ALK fusion proteins were detected in the same tumor cells through immunohistochemical analysis. Investigation of the molecular mechanisms of concomitant EGFR mutation and the EML4-ALK rearrangement in the same tumor cell can help discover an appropriate treatment for these patients.
Methods:
PC-9 cells, expressing EGFR exon 19 deletion, were transfected with EML4-ALK variant 3a (v3a) and variant 3b (v3b) separately and selected, and the effect of EGFR and ALK inhibitors was evaluated in vitro and in vivo.
Results:
PC-9_v3a-gef and PC-9_v3b-gef cells were resistant to gefitinib and ALK inhibitors alone, but ALK inhibitors enhanced gefitinib-induced cytotoxicity. In animal studies, gefitinib completely inhibited the tumor growth in PC-9_vector cells but not in PC-9_v3a-gef and PC-9_v3b-gef cells. A combination of ALK inhibitor and gefitinib was found to be more potent than gefitinib alone in PC-9_v3a-gef and PC-9_v3b-gef cells. Furthermore, combination treatment with osimertinib and ceritinib caused a decrease in liver tumor size of the patient with liver metastases.
Conclusions:
Our data suggest that combination treatment with EGFR and ALK inhibitors can be a therapeutic strategy for treating NSCLC with concomitant EGFR mutation and EML4-ALK rearrangement.
Insights
This study found that combining EGFR and ALK inhibitors is effective for treating non-small cell lung cancer (NSCLC) with both EGFR mutations and EML4-ALK rearrangements, especially after resistance develops to single-agent treatments.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Driver gene mutations in non-small cell lung cancer (NSCLC) are often considered mutually exclusive.
- However, some NSCLC patients present with both epidermal growth factor receptor (EGFR) mutations and echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangements.
- Concomitant mutations can arise after resistance to targeted therapies, complicating treatment strategies.
Purpose of the Study:
- To investigate the efficacy of combined EGFR and ALK inhibition in NSCLC models harboring both EGFR mutations and EML4-ALK rearrangements.
- To evaluate therapeutic strategies for patients who develop resistance to EGFR tyrosine kinase inhibitors.
Main Methods:
- PC-9 cells with an EGFR exon 19 deletion were transfected with EML4-ALK variants (3a and 3b).
- In vitro and in vivo studies assessed the effects of EGFR inhibitors (gefitinib, osimertinib) and ALK inhibitors (ceritinib) alone and in combination.
- Immunohistochemical analysis confirmed the presence of both EGFR-mutant and ALK fusion proteins in the same tumor cells.
Main Results:
- Cells with both EGFR mutations and EML4-ALK rearrangements (PC-9_v3a-gef, PC-9_v3b-gef) showed resistance to single-agent gefitinib or ALK inhibitors.
- Combination therapy with ALK inhibitors and gefitinib demonstrated enhanced cytotoxicity and potent tumor growth inhibition in vitro and in vivo.
- Combination treatment with osimertinib and ceritinib led to a reduction in liver tumor size in a patient with metastases.
Conclusions:
- Combination treatment with EGFR and ALK inhibitors represents a promising therapeutic strategy for NSCLC patients with concomitant EGFR mutations and EML4-ALK rearrangements.
- This approach may overcome resistance mechanisms developed against single-targeted therapies.
- Further investigation into molecular mechanisms can guide optimal treatment selection for these complex cases.
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