(Health Korea News / Lee Soon-ho) A Japanese research team has drawn attention by suggesting a clue to overcoming resistance to the lung cancer drug ‘Leclaza’ developed by Yuhan Corporation. ‘Leclaza (ingredient name: Lazertinib)’ is a third-line treatment used by patients who have already developed resistance to other anticancer drugs. Since there are not many anticancer drugs that can be used after developing resistance to ‘Leclaza’, follow-up research is needed to confirm whether the results of this study can be applied to actual clinical trials.
A research team comprised of professors from the Department of Respiratory Medicine and the Department of Drug Discovery Medicine at Kyoto Prefecture University School of Medicine in Japan recently published a research paper in the official journal of the Japanese Cancer Society, Cancer Science, which states that inhibiting AXL and MCL-1 can effectively prevent the development of resistance to ‘Leclaza’ in EGFR mutant lung cancer cells.
논문 제목은 ‘Initial AXL and MCL-1 inhibition contributes to abolishing lazertinib tolerance in EGFR-mutant lung cancer cells’이다.
AXL is a protein that plays an important role in acquired resistance to EGFR-TKI anticancer drugs and is involved in poor prognosis. In non-small cell lung cancer, AXL is overexpressed and overactivated. MCL-1 is an anti-apoptotic protein that is thought to cause chemotherapy resistance and rapid tumor growth.
The research team investigated the efficacy of ‘Leclaza’ after treating 7 human non-small cell lung cancer cell lines with EGFR mutations. As a result, ‘Leclaza’ showed high sensitivity in most cells, but in the PC-9 cell line with EGFR exon 19 deletion, cell growth was not completely inhibited even when exposed to ‘Leclaza’ at high concentrations for a long period of time.
Accordingly, the research team screened factors related to resistance to ‘Reclaza’ and confirmed that among 56 siRNAs targeting receptor-type tyrosine kinase, suppressing AXL gene expression had a remarkable synergistic effect in reducing PC-9 cell viability, and conducted research focusing on this.
The study was conducted to investigate the synergistic effect of combining ‘Leclaza’ with an AXL inhibitor in EGFR mutant non-small cell lung cancer cells. The results of the study showed that in all cell lines with high AXL expression, combination treatment with an AXL inhibitor showed better efficacy than when ‘Leclaza’ was used alone.
“These results highlight the importance of AXL and its role as a biomarker for resistance to Leclaza in EGFR mutant non-small cell lung cancer cells,” the research team explained.
However, despite the long-term effects of the combination therapy of ‘Leclaza’ and AXL inhibitor, resistance occurred again after a certain period of time, and these cell lines showed a common feature of increased MCL-1 expression after ‘Leclaza’ treatment.
Accordingly, the research team suppressed the expression of MCL-1, and as a result, it was shown that cell death increased during combined treatment with ‘Reclaza’ and AXL inhibitor. When MCL protein was additionally suppressed, the effect of inhibiting cell viability was further enhanced.
“These results demonstrate that MCL-1 protein is important for apoptosis resistance during combined treatment with Leclaza and an AXL inhibitor in EGFR mutant non-small cell lung cancer cells,” the research team said.
Then, “when the YAP protein involved in regulating MCL-1 was neutralized and combined treatment with ‘Leclaza’ and an AXL inhibitor inhibited MCL-1 expression, these results indicate that the resistance to the combination of ‘Leclaza’ and an AXL inhibitor increased due to the simultaneous activation of the YAP–MCL-1 axis in EGFR mutant NSCLC cells,” he explained.
After completing all observations, the research team concluded that triple therapy using MCL-1 or YAP inhibitors together with ‘Leclaza’ and an AXL inhibitor significantly reduced cell viability and increased cell death rate, suggesting an initial dual inhibition strategy of AXL and YAP/MCL-1 as an effective way to overcome ‘Leclaza’ resistance.
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