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

Pdf Summary

This study investigates the underlying mechanisms of primary resistance to ALK tyrosine kinase inhibitors (TKIs) in patients with ALK fusion positive lung cancer. The researchers conducted a genome-wide CRISPR screening targeting three ALK-TKIs (Lorlatinib, Alectinib, Ensartinib) in ALKNSCLC cells. They found that loss of the EPHA2 gene induces primary resistance to Lorlatinib through sustained activation of the MAPK signaling pathway. The study also revealed that EPHA2 is associated with RAS oncogenic activity.<br /><br />The researchers used the Human GeCKOv2 CRISPR knockout pooled library to identify genes responsible for resistance to ALK-TKIs. They found that EPHA2-RHOA inactivation led to resistance to Lorlatinib but not to Ensartinib or Alectinib. Further analysis showed that Lorlatinib downgraded the RAS-MAPK signaling pathway and EPHA2 expression. Knocking out EPHA2 in NSCLC cells impaired Lorlatinib sensitivity and resulted in sustained MAPK activation. Pharmacological inhibition of the MAPK pathway partially restored Lorlatinib sensitivity in EPHA2-knockout cells.<br /><br />The findings suggest that EPHA2 is a crucial gene for the therapeutic efficacy of Lorlatinib, acting as a downstream indicator and a significant suppressor of oncogenic RAS bypass. Loss of EPHA2 leads to Lorlatinib resistance due to the lack of negative feedback to MAPK signaling. The study highlights the potential of dual-targeted therapy with MEK inhibitor Selumetinib as a rational treatment strategy for patients with EPHA2 deficiency.<br /><br />Overall, this study provides insights into the mechanistic understanding of primary resistance to ALK inhibitors and suggests EPHA2 as a potential biomarker for selecting appropriate candidates for Lorlatinib treatment in patients with ALK fusion positive lung cancer.

Asset Subtitle

Anlin Li

Meta Tag

Speaker Anlin Li

Topic Metastatic NSCLC: Targeted Therapy - FUSIONS

Keywords

ALK tyrosine kinase inhibitors

primary resistance

ALK fusion positive lung cancer

genome-wide CRISPR screening

EPHA2 gene

MAPK signaling pathway

RAS oncogenic activity

Human GeCKOv2 CRISPR knockout pooled library

Lorlatinib sensitivity

dual-targeted therapy