Singapore's Research Triumph: Unmasking Lung Cancer's Protective Mechanism

Singaporean scientists have made a pivotal discovery in the fight against lung cancer, identifying a sophisticated 'bodyguard system' that shields mutant proteins from destruction in cancer cells. This breakthrough, led by researchers at the A*STAR Institute of Molecular and Cell Biology (IMCB), reveals how non-small cell lung cancer (NSCLC) cells with epidermal growth factor receptor (EGFR) mutations evade targeted therapies. Published in the prestigious journal Science Advances on January 21, 2026, the study opens doors to new combination treatments that could overcome drug resistance, a major hurdle for patients.

Lung cancer remains Singapore's top cancer killer among men, accounting for 24.6% of male cancer deaths, and the third leading cause in women at 15.9%. EGFR mutations drive up to 40-60% of adenocarcinoma cases in Southeast Asia, particularly among non-smokers and women, making this research especially relevant to the local population.

The Science Behind the Bodyguard: P2Y2 Receptor and Integrin β1 Team Up

At the heart of this discovery is the P2Y2 receptor (purinergic receptor P2Y2), a cell surface protein activated by excess adenosine triphosphate (ATP) released by cancer cells. Once activated, P2Y2 recruits integrin β1, a cell adhesion molecule, to form a protective complex around the mutant EGFR protein. This 'bodyguard' barrier prevents the faulty protein from entering the cell's lysosomal degradation pathway, where it would normally be broken down. Instead, the stable mutant EGFR continues signaling unchecked cell growth and survival.

The process unfolds step-by-step: First, EGFR-mutant cells produce and export high levels of extracellular ATP—threefold higher than normal cells. ATP binds to P2Y2, triggering crosstalk with integrin β1 via endosomal enrichment. This complex stabilizes EGFR mutants, even those resistant to tyrosine kinase inhibitors (TKIs) like osimertinib. Researchers confirmed this in patient-derived tumor samples from 29 individuals, showing elevated P2Y2 and integrin β1 in cancerous tissue versus healthy adjacent areas.

Groundbreaking Methods: Genome-Wide Screen Pinpoints the Target

To uncover this mechanism, the team employed a genome-wide RNA interference (RNAi) screen scanning over 21,000 genes. They sought stabilizers specific to EGFR mutants like the common exon 19 deletion (EGFR-19del). P2Y2 emerged as a top hit, with knockdown causing rapid degradation of mutant EGFR via lysosomes, reducing cell proliferation and invasion selectively in mutant cells.

• RNAi screen identified 110 candidate stabilizers, P2Y2 validated as key.
• ATP scavenging with apyrase or P2Y2 antagonists destabilized EGFR mutants.
• RGD peptides disrupting integrin binding mimicked the effect.
• In vivo xenograft models showed tumor shrinkage upon targeting.

This rigorous approach highlights Singapore's prowess in functional genomics, a strength in its higher education and research ecosystem.

A*STAR IMCB Leads with NUS and NCCS Collaboration

The study was spearheaded by Professor Wanjin Hong, Senior Principal Investigator at A*STAR IMCB and recipient of Singapore's President's Science Award, alongside Senior Scientist Dr. Gandhi Boopathy and PhD student Yafei Du (SINGA scholar). Collaborators included the National University of Singapore (NUS), National Cancer Centre Singapore (NCCS), China Medical University (Taiwan), and the Centre de Recherche en Cancérologie de Marseille (France).

"Cancer cells deploy molecular 'bodyguards' to shield the mutant protein," explained Dr. Boopathy. Prof. Hong added, "Targeting P2Y2 attacks the scaffolding keeping it stable, potentially preventing resistance." Such interdisciplinary partnerships exemplify how Singapore's universities like NUS integrate with research institutes like A*STAR to drive translational cancer research. For aspiring researchers, explore higher ed jobs in Singapore's vibrant biomedical sector or Singapore academic opportunities.

Promising Treatment Avenue: Kaempferol from Everyday Vegetables

A highlight is kaempferol, a flavonoid abundant in broccoli, kale, and other cruciferous vegetables. In drug-resistant human lung tumor models (e.g., H1975 with T790M/C797S mutations), daily kaempferol treatment over 24 days significantly reduced tumor volume, sparing normal EGFR tumors. It disrupts the P2Y2-integrin axis without toxicity.

Combining P2Y2 inhibitors with focal adhesion kinase (FAK) blockers synergized against triple-mutant cells. While clinical trials are needed, this natural compound offers hope for adjunct therapy in EGFR-driven NSCLC. Prior studies link cruciferous veggies to lower cancer risk, aligning with dietary prevention strategies.

Photo by Galen Crout on Unsplash

Lung Cancer Burden in Singapore: Why This Matters Locally

From 1968-2021, Singapore recorded over 53,000 lung cancer cases, mostly late-stage (81.6%). Incidence is rising, especially among never-smokers, with EGFR mutations predominant. This IMCB breakthrough addresses a regional gap, where TKIs fail due to resistance in nearly all patients.

Singapore's National Cancer Registry notes declining death rates (21% since 2012) thanks to early detection and therapies, but resistance remains key. Research like this bolsters the nation's goal to halve cancer mortality by 2040.

Singapore's Higher Ed Ecosystem Fuels Cancer Research Excellence

A*STAR IMCB's work thrives through ties with NUS and NTU, fostering talent via SINGA scholarships. NUS's Cancer Science Institute (CSI) complements such efforts, training PhDs in precision oncology. These collaborations position Singapore as Asia's biotech hub, attracting global talent.

Prospective faculty can find professor jobs or research positions here. Students, check higher ed career advice for paths in biomedical sciences.

Challenges and Future Directions in Overcoming Resistance

• Triple mutants (e.g., 19del/T790M/C797S) challenge current TKIs.
• P2Y2 inhibitors could restore sensitivity.
• Clinical trials needed for kaempferol combos.
• Personalized medicine via biomarkers like P2Y2 expression.

Experts foresee trials within 2-3 years, potentially integrating with Singapore's CLARION program ($25M for Asian lung cancer research).

Stakeholder Perspectives: From Patients to Policymakers

Patients at NCCS praise targeted therapies but seek resistance solutions. Policymakers highlight RIE2030 investments ($37B in quantum/biotech). Prof. Hong's lab exemplifies how basic research translates clinically.

Opportunities for Researchers and Students in Singapore

This discovery underscores career prospects in Singapore's cancer research. NUS offers PhD programs in oncology; A*STAR fellowships abound. Visit Rate My Professor for insights or higher ed faculty jobs. For jobs, see university jobs and postdoc positions.

Actionable insight: Aspiring scientists, pursue SINGA for IMCB-like projects. Institutions like NUS equip you for breakthroughs.

Photo by Hyundai Motor Group on Unsplash

Looking Ahead: Transforming Lung Cancer Care in Asia

The P2Y2-integrin axis targets a vulnerability in 50%+ Asian NSCLC cases. With Singapore's ecosystem—NUS, A*STAR, NCCS—poised for trials, this could redefine treatment. Stay informed via higher education news and explore career advice to join the fight. Engage in comments below or search higher ed jobs today.