Synergistic Inhibition of Drug Resistant KRAS Mutant Non-Small Cell Lung Cancer by Co-Targeting AXL and SRC

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• KRAS-mutated non-small cell lung cancer (NSCLC) often develops resistance to targeted therapies like monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs).
• Activation of the AXL-SRC-Akt signaling pathway is a potential mechanism driving this acquired resistance.
• AXL has been identified as a bypass resistant gene in this context, interacting with KRAS and SRC activity.

Purpose of the Study:

• To investigate the role of AXL as a bypass resistant gene in KRAS-mutated NSCLC.
• To evaluate the efficacy of co-inhibiting AXL and SRC in overcoming therapeutic resistance.
• To elucidate the effects of AXL and SRC co-inhibition on KRAS activity and apoptosis.

Main Methods:

• Utilized Dasatinib and SGI-7079 for co-inhibition of SRC and AXL, respectively.
• Conducted in vitro studies using four NSCLC cell lines with AXL suppression via siRNA and CRISPR-Cas9 knockout.
• Performed gene-protein expression analysis (Western blot), apoptosis assays (cytochrome release), cytotoxicity assays (MTT), and in vivo validation using A549 xenografts.

Main Results:

• Dual inhibition of AXL and SRC significantly reversed therapeutic resistance in both in vitro and in vivo models.
• The combined inhibition strategy demonstrated effectiveness in overcoming resistance mechanisms in NSCLC.

Conclusions:

• Co-inhibition of AXL and SRC synergistically reduces KRAS activity in NSCLC.
• This dual inhibition strategy effectively induces apoptosis in cancer cells, offering a potential therapeutic approach for resistant NSCLC.