Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as osimertinib, is a significant challenge in treating EGFR mutated lung cancer (EGFRmut-LC).
• The precise mechanisms underlying drug tolerance and acquired resistance to EGFR-TKIs remain incompletely understood.

Purpose of the Study:

• To elucidate the mechanisms of osimertinib tolerance in AXL-low expressing EGFRmut-LC cells.
• To investigate the role of insulin-like growth factor-1 receptor (IGF-1R) signaling in mediating this tolerance.
• To evaluate the therapeutic potential of combining IGF-1R inhibition with osimertinib for overcoming resistance.

Main Methods:

• Comparative analysis of osimertinib sensitivity in AXL-low versus AXL-high EGFRmut-LC cells.
• Investigation of molecular pathways involved in osimertinib tolerance, focusing on IGF-1R and its transcriptional regulator FOXA1.
• Assessment of combined osimertinib and IGF-1R inhibition in EGFRmut-LC cell-derived and patient-derived xenograft models.

Main Results:

• A small population of AXL-low EGFRmut-LC cells emerged with osimertinib tolerance.
• This tolerance was mediated by increased expression and phosphorylation of IGF-1R, induced by FOXA1.
• Combined transient IGF-1R inhibition and continuous osimertinib treatment eradicated tumors and prevented regrowth in preclinical models.

Conclusions:

• IGF-1R signaling, driven by FOXA1, plays a critical role in mediating osimertinib tolerance in EGFRmut-LC.
• Targeting IGF-1R in combination with osimertinib represents a promising strategy to overcome acquired resistance.
• This combination therapy holds potential for significantly improving outcomes in patients with EGFRmut-LC.