Analysing the kinome of non-small cell lung cancer cells: new biomarkers of chemo-immunoresistance, new therapeutic targets

Non–small–cell lung cancer (NSCLC) accounts for approximately 85% of all lung malignancies and remains the leading cause of cancer-related death worldwide. Despite significant progress in targeted and immune-based therapies, the majority of patients still rely on platinum-based chemotherapy, whose efficacy is often limited by drug resistance. One primary mechanism of chemoresistance involves ATP-binding cassette (ABC) transporters: ABCB1 and ABCC1 promote drug efflux, whereas ABCA1 loss impairs immune recognition by Vγ9Vδ2 T-lymphocytes. However, the upstream molecular regulators linking chemotherapy resistance and immune evasion remain poorly understood. Through a CRISPR-Cas9 kinome-wide screen, this study identifies interleukin-1 receptor–associated kinase 1 (IRAK1) as a crucial regulator of chemo-immuno-resistance in NSCLC. Silencing IRAK1 reprograms the ABC transporter profile, increasing tumour sensitivity to cisplatin and docetaxel, and restoring immune-mediated cytotoxicity. Mechanistically, IRAK1 promotes ABCB1 and ABCC1 expression via the IL-1R/MyD88/TRAF6/NFκB and ERK/AP-1 pathways, while it suppresses ABCA1 through LXRα inhibition. In humanised NSG Hu-CD34⁺ mouse models, IRAK1 silencing and treatment with novel small-molecule IRAK1 inhibitors delayed tumour growth, increased apoptosis, and enhanced infiltration of CD8⁺ and Vγ9Vδ2 T-cells, confirming its dual chemo- and immuno-sensitising role in vivo. Patient sample analysis showed that high IRAK1 levels were linked to high ABCC1, low ABCA1, and poor overall survival, establishing IRAK1 as a negative prognostic and predictive biomarker. Phosphoproteomics and INKA analyses highlighted signalling rewiring in receptor tyrosine kinases after IRAK1 loss, suggesting new drug combination strategies. For instance, we discovered that dual EGFR/ERK inhibition synergistically restored platinum sensitivity. Overall, these findings identify IRAK1 as a clinically relevant and druggable target, supporting translational approaches that combine IRAK1 inhibitors with platinum-based chemotherapy and immunotherapy and/or targeted therapy to overcome resistance and improve the outcome of patients with highly refractory NSCLC.