Targeting ERBB3 and AKT to overcome adaptive resistance in EML4-ALK-driven non-small cell lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion drives oncogenesis in 5% of non-small cell lung cancer (NSCLC).
• ALK-tyrosine kinase inhibitors (TKIs) are effective treatments for EML4-ALK-positive NSCLC, but acquired resistance remains a clinical challenge.

Purpose of the Study:

• To investigate kinase responses in EML4-ALK-positive NSCLC cells upon acute inhibition with the ALK TKI lorlatinib (LOR).
• To identify potential therapeutic targets to overcome resistance to ALK-targeted therapies in NSCLC.

Main Methods:

• Utilized phosphopeptide chip array and upstream kinase prediction analysis.
• Examined kinase responses in EML4-ALK V1 and V3 NSCLC cell lines after lorlatinib treatment.
• Assessed the effects of dual inhibition of ALK with ERBB or AKT.

Main Results:

• Upregulation of phosphorylated tyrosine peptides, including ERBB and AKT proteins, was observed upon ALK-TKI treatment.
• Dual inhibition of ALK and ERBB/AKT disrupted RAS/MAPK and AKT/PI3K signaling pathways, enhancing apoptosis.
• EML4-ALK cells resistant to lorlatinib showed sensitivity to ERBB and AKT inhibition.

Conclusions:

• AKT and ERBB3 play crucial roles in regulating signaling pathways following acute lorlatinib treatment.
• Targeting ERBB and AKT concurrently with ALK inhibitors may represent a viable strategy to prevent or overcome adaptive resistance in EML4-ALK-positive NSCLC.