Scientists from Singapore's ASTAR Institute of Molecular and Cell Biology (ASTAR IMCB) have identified a mechanism that contributes to drug resistance in lung cancer cells with mutations in the EGFR (epidermal growth factor receptor) gene. The research, published in Science Advances, details how a newly discovered survival pathway protects faulty EGFR proteins from degradation. Disrupting this mechanism, including through the use of the natural compound kaempferol, was shown to reduce tumor size in laboratory models.
Background on Lung Cancer and Treatment Resistance
Lung cancer remains a leading cause of cancer-related deaths globally. A significant number of cases, particularly adenocarcinoma in Southeast Asia (40–60%), are associated with EGFR gene mutations. These mutations promote uncontrolled cell growth and division. While initial targeted drug therapies are often effective for patients with EGFR mutations, most eventually develop resistance. A long-standing challenge has been understanding why the faulty proteins produced by mutant EGFR are unusually stable and evade typical cellular degradation processes.
Discovery of a Protective Mechanism
To investigate the stability of these mutant EGFR proteins, researchers conducted a genome-wide screen of over 21,000 genes. They discovered that cancer cells release an excess of ATP (adenosine triphosphate) into their environment. This excess ATP activates a receptor called P2Y2, located on the cell surface. The P2Y2 receptor then recruits integrin β1.
Together, P2Y2 and integrin β1 form a protective barrier around the mutant EGFR protein. This barrier prevents the faulty protein from being transported to the cell's normal degradation pathway or recycling center, allowing it to remain active and continue driving cancer growth. Elevated levels of both P2Y2 and integrin β1 were confirmed in tumor tissue samples from 29 lung cancer patients, when compared to adjacent healthy tissue.
Potential Therapeutic Approaches
Experiments demonstrated that removing the P2Y2 receptor in drug-resistant cancer cells led to a near-complete loss of the mutant EGFR protein. The research team also investigated kaempferol, a natural compound found in vegetables such as kale and broccoli.
In laboratory models featuring drug-resistant human lung tumors, daily treatment with kaempferol significantly reduced tumor size over a 24-day period. The treatment specifically targeted cancer cells with EGFR mutations and showed no detectable effect on tumors with normal EGFR.
Researchers suggested that targeting the P2Y2 system could potentially be used alongside existing treatments to overcome or prevent drug resistance. The location of the P2Y2 receptor on the cell surface was noted as a potential advantage for drug targeting.
The study was a collaborative effort involving A*STAR IMCB, the National University of Singapore, National Cancer Centre Singapore, China Medical University in Taiwan, and the Centre de Recherche en Cancérologie de Marseille in France.