2023 World Conference on Lung Cancer (Posters)-P2.10. Loss of EPHA2 Induces Primary Lorlatinib Resistance Through Sustained MAPK Activation<b></b>

P2.10. Loss of EPHA2 Induces Primary Lorlatinib Resistance Through Sustained MAPK Activation - PDF(Slides)

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Researchers at Sun Yat-sen University Cancer Center in China have identified a gene, EPHA2, that plays a crucial role in conferring therapeutic efficacy to the ALK tyrosine kinase inhibitor, Lorlatinib. The study, conducted on non-small cell lung cancer (NSCLC) cells, found that loss of EPHA2 led to primary resistance to Lorlatinib due to the lack of negative feedback to the MAPK pathway. The researchers used a genome-wide CRISPR screening approach and RNA-seq to investigate the genes responsible for resistance to three ALK-TKIs - Lorlatinib, Alectinib, and Ensartinib - in ALKNSCLC cells. They then used CRISPR/Cas9-mediated gene editing to generate EPHA2-knockout NSCLC cells and evaluated their sensitivity to Lorlatinib both in vitro and in vivo.<br /><br />The study found that EPHA2 inactivation induced resistance to Lorlatinib, but not to Ensartinib or Alectinib. The absence of EPHA2 significantly impaired Lorlatinib sensitivity in NSCLC cells and was accompanied by sustained activation of the MAPK signaling. The findings suggest that loss of EPHA2 leads to Lorlatinib resistance through sustained MAPK activation.<br /><br />The researchers propose that the dual-targeted therapy with MEK inhibitor Selumetinib may be a rational treatment strategy for patients with EPHA2 deficiency. They also suggest that the findings can help in selecting appropriate candidates for Lorlatinib treatment.<br /><br />In conclusion, EPHA2 is identified as a crucial gene in conferring therapeutic efficacy to Lorlatinib in ALK fusion positive lung cancer. Loss of EPHA2 leads to primary resistance to Lorlatinib due to sustained activation of the MAPK pathway. These findings provide supportive evidence for selecting appropriate candidates for Lorlatinib treatment.

Asset Subtitle

Anlin Li

Meta Tag

Speaker Anlin Li

Topic Metastatic NSCLC: Targeted Therapy - FUSIONS

Keywords

gene

EPHA2

therapeutic efficacy

ALK tyrosine kinase inhibitor

Lorlatinib

non-small cell lung cancer

NSCLC

MAPK pathway

CRISPR screening

RNA-seq