Chemotherapy confers a conserved secondary tolerance to EGFR inhibition via AXL-mediated signaling bypass

Area of Science:

• Oncology
• Molecular Biology
• Drug Resistance Mechanisms

Background:

• Drug resistance is a primary cause of cancer therapy failure, especially in disseminated cancers.
• Simultaneous resistance to multiple drugs fuels cancer relapse.
• Understanding co-resistance mechanisms is crucial for developing effective cancer treatments.

Purpose of the Study:

• To investigate co-resistance signatures between antimitotic drugs (AMDs) and receptor tyrosine kinase inhibitors (RTKs).
• To probe mechanisms of secondary drug resistance in cancer.
• To identify therapeutic strategies to overcome acquired resistance.

Main Methods:

• Mapping co-resistance ranks across multiple drug pairs in cancer cell lines.
• Analyzing genomic alterations and gene expression signatures of EGFR and AXL.
• Utilizing acquired resistance models to antimitotic drugs (paclitaxel, epothilone B).
• Investigating the role of AXL degradation in drug persistence and resistance.

Main Results:

• Widespread co-resistance to gefitinib (an EGFR-TKI) was identified in cell lines resistant to 11 AMDs.
• EGFR and AXL RTKs showed similar alteration and expression patterns.
• AXL acts as a bypass signal in a drug-tolerant persister state, conferring collateral resistance to gefitinib.
• Delayed AXL degradation stabilized this persister state, leading to stable resistance.
• A new EGFR-TKI candidate (YD) demonstrated the potential to suppress AXL bypass-driven collateral resistance.

Conclusions:

• Chemoresistant cancer cells utilize the AXL bypass pathway upon EGFR inhibition to enter a persister state.
• This AXL-mediated persistence facilitates the evolution of resistance to EGFR-TKIs.
• Pharmacological targeting of AXL degradation offers a potential strategy to overcome acquired resistance to EGFR-TKIs.