Newly discovered survival pathway explains stubborn EGFR-driven lung cancers

Scientists from A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB) have identified why certain lung cancer cells become highly resistant to treatment after developing mutations in a key gene called EGFR (epidermal growth factor receptor). In a study published in Science Advances, the researchers revealed a previously unknown survival mechanism and demonstrated that disrupting it can shrink tumors in laboratory models.

Lung cancer is the leading cause of cancer deaths globally. Many cases are driven by mutations in the EGFR gene, which causes cells to grow and divide uncontrollably. In Southeast Asia, these mutations are found in up to 40–60% of a common type of lung cancer called adenocarcinoma. While targeted drugs initially work well against these cancers, nearly all patients eventually stop responding.

Scientists have long puzzled over why the faulty proteins produced by mutant EGFR are so stable – while normal proteins are recycled via degradation, these mutant versions persist far longer than they should.

Genome-wide screen reveals how cancer cells protect themselves

The researchers screened more than 21,000 genes to identify what protects these mutant proteins from being broken down. They discovered that cancer cells flood their surroundings with ATP (adenosine triphosphate), a molecule normally used for energy. This excess ATP switches on a receptor called P2Y2, which then recruits a partner protein called integrin β1 to form a protective barrier around the mutant EGFR.

This barrier stops the faulty protein from reaching the cell's "recycling centre," where it would normally be broken down. Instead, the protected protein remains active and continues driving cancer growth. The team confirmed these findings in human cancers by examining tissue samples from 29 lung cancer patients, where both P2Y2 and integrin β1 were found at elevated levels in tumors compared to adjacent healthy tissue.

"We found that cancer cells deploy molecular 'bodyguards' to shield the mutant protein from being broken down," said Dr Gandhi Boopathy, Senior Scientist at A*STAR IMCB and co-corresponding author of the study. "The good news is that P2Y2 sits on the cell surface, so it's much easier for drugs to reach compared to targets hidden deep inside the cell."

Natural compound shows promise against drug-resistant tumors

The team showed that removing this protective system could stop cancer in its tracks. When they knocked out the P2Y2 receptor in drug-resistant cancer cells, it led to an almost complete loss of the mutant EGFR protein.

The researchers also tested kaempferol, a natural compound found in vegetables like kale and broccoli. In laboratory models with drug-resistant human lung tumors, daily treatment with kaempferol significantly shrank tumors over 24 days. Crucially, the treatment targeted only the cancer cells carrying EGFR mutations while having no detectable effect on tumors with normal EGFR.

"By targeting the P2Y2 system, we're not just attacking the mutation itself, but the scaffolding that keeps it stable," said Professor Wanjin Hong, Senior Principal Investigator at A*STAR IMCB and co-corresponding author. "This approach could potentially work alongside current drugs to overcome or even prevent resistance, opening up a new way to tackle drug resistance when existing treatments stop working."

The study was led by Prof Wanjin Hong, a President's Science Award recipient whose lab has pioneered research into how cancer cells evade destruction. The co-first author Yafei Du is a PhD student supported by the Singapore International Graduate Award (SINGA). The research was a collaborative effort involving researchers from A*STAR, the National University of Singapore, and the National Cancer Centre Singapore, as well as partners at China Medical University in Taiwan and the Centre de Recherche en Cancérologie de Marseille in France.