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  3. 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)

  • Sci Adv. 2026 Jan 23;12(4):eadv3980. doi: 10.1126/sciadv.adv3980.
Yafei Du 1 2,  Wenjing Wang 1,  Hui Chin Goh 1,  Thamil Selvan Vaiyapuri 1,  Anandhkumar Raju 1,  Yu-Chun Hsiao 3,  Cheng Chun Wang 1,  Vanisha Agrawal 1,  Noorul Farzana Mohideen 1,  Norhidayah Binte Mohd Mazian 1,  Feride Karatekin 1,  Wendy Kehan Wang 1,  Manikandan Lakshmanan 1,  Komal Gupta 1 4,  Han Chang 5 6,  Xavier Le Guezennec 1,  Frederic Bard 1 7,  Daniel S W Tan 4,  Vinay Tergaonkar 1,  Mien-Chie Hung 3,  Xiaogang Liu 2 8,  Wanjin Hong 1,  Gandhi T K Boopathy 1
Affiliations

Affiliations

  • 1 Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore.
  • 2 Department of Chemistry, National University of Singapore, Singapore, Singapore.
  • 3 Center for Molecular Medicine, Research Center for Cancer Biology, and Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
  • 4 National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore.
  • 5 School of Medicine, China Medical University, Taichung, Taiwan.
  • 6 Department of Pathology, China Medical University Hospital, Taichung, Taiwan.
  • 7 Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université, Inserm, CNRS, Institut Paoli-Calmettes, Equipe Leader Fondation ARC 2021, Marseille, France.
  • 8 Institute of Materials Research and Engineering (IMRE), A*STAR, 2 Fusionopolis Way, Singapore 138634, Singapore.
PMID: 41564171 DOI: 10.1126/sciadv.adv3980
Abstract

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.

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