A genome-wide genetic screen reveals the P2Y2-integrin axis as a stabilizer of EGFR mutants in non–small cell lung cancer (NSCLC)

A genome-wide genetic screen reveals the P2Y2-integrin axis as a stabilizer of EGFR mutants in non–small cell lung cancer (NSCLC)

Science Advances

10.1126/sciadv.adv3980

https://doi.org/10.1126/sciadv.adv3980

Yafei Du, Wenjing Wang, Hui Chin Goh, Thamil Selvan Vaiyapuri, Anandhkumar Raju, Yu-Chun Hsiao, Cheng Chun Wang, Vanisha Agrawal, Noorul Farzana Mohideen, Norhidayah Binte Mohd Mazian, Feride Karatekin, Wendy Kehan Wang, Manikandan Lakshmanan, Komal Gupta, Han Chang, Xavier Le Guezennec, Frederic Bard, Daniel S. W. Tan, Vinay Tergaonkar, Mien-Chie Hung, Xiaogang Liu, Wanjin Hong, Gandhi T. K. Boopathy

Cell Biology, Biochemistry

21 January 2026

Du, Y., Wang, W., Goh, H. C., Vaiyapuri, T. S., Raju, A., Hsiao, Y.-C., Wang, C. C., Agrawal, V., Mohideen, N. F., Mohd Mazian, N. B., Karatekin, F., Wang, W. K., Lakshmanan, M., Gupta, K., Chang, H., Le Guezennec, X., Bard, F., Tan, D. S. W., Tergaonkar, V., … Boopathy, G. T. K. (2026). A genome-wide genetic screen reveals the P2Y2-integrin axis as a stabilizer of EGFR mutants in non–small cell lung cancer (NSCLC). Science Advances, 12(4). https://doi.org/10.1126/sciadv.adv3980

Activating mutations in the epidermal growth factor receptor (EGFR) gene drive non–small cell lung cancer (NSCLC). Oncogenic EGFR mutants are ligand-independent and more stable, but the underlying mechanism remains unclear. We hypothesized that EGFR mutants selectively leverage cellular stabilizers to evade degradation. Genome-wide RNA interference screens identified genes (encoding for stabilizers) responsible for mutant EGFR stability, with P2Y2 receptor (P2Y2) emerging as a bona fide stabilizer. Mechanistically, high extracellular adenosine triphosphate (ATP) levels transactivate EGFR mutants via P2Y2 activation, previously shown to signal through Src kinase–dependent EGFR phosphorylation. Our study reveals that ATP-driven P2Y2 activation stabilizes EGFR mutants by forming a P2Y2-integrin β1-EGFR complex enriched in endosomes. Targeting this axis destabilizes EGFR mutants and offers a strategy against drug resistance. Elevated P2Y2 and integrin β1 expression in patients with NSCLC implies clinical relevance. Our results provide previously unidentified insight that EGFR mutants enhance extracellular ATP levels to activate P2Y2-integrin for enhanced stability of EGFR mutants to drive the oncogenic program.

Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

This research / project is supported by the Agency for Science, Technology and Research (ASTAR) - Career Development Award/Fund
Grant Reference no. : 202D800038

This research / project is supported by the National Research Foundation (NRF) - Competitive Research Programme (CRP)
Grant Reference no. : NRF-CRP28-2022-0001

This research / project is supported by the A*STAR IMCB - IMCB Discovery Catalyst Grant 2025
Grant Reference no. : NA

This research / project is supported by the Ministry of Health, National Medical Research Counil - Open Fund individual Research Grant
Grant Reference no. : MOh-OFiRG24jan-0003

This research / project is supported by the A*STAR Biomedical Research Council - Central Research Fund
Grant Reference no. :

https://oar.a-star.edu.sg/communities-collections/articles/22751

2375-2548

Institute of Molecular and Cell Biology

https://doi.org/10.1126/sciadv.adv3980