When a major highway is shut down and traffic grinds to a halt, resourceful drivers find detours through side streets. Similarly, though cancer drugs can be initially effective at stopping cancer cells from growing, these cells are highly adaptable and eventually find alternate pathways to reactivate their growth.
Such drug resistance is a key challenge in non-small cell lung cancer (NSCLC), as patients have limited treatment options once their tumours become resistant to standard therapies.
“Many NSCLC cases are driven by mutant EGFR, a protein which evades the cell’s natural disposal system and sends continuous signals for cancer cells to multiply,” explained Wanjin Hong, a Principal Investigator at the A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB). “While we have targeted therapies that block mutant EGFR activity very effectively, it eventually bypasses these drugs, causing tumours start growing again.”
Together with researchers from A*STAR IMCB; the A*STAR Institute of Materials Research and Engineering (A*STAR IMRE); National Cancer Centre Singapore (NCCS); and China Medical University, Taiwan; Hong and A*STAR IMCB Senior Scientist Gandhi T.K. Boopathy recently conducted a genome-wide genetic screen to investigate how mutant EGFR is stabilised in NSCLC, uncovering a new way to shut down the protein.
First, the team systematically downregulated thousands of genes across the entire human genome, one by one, to see which missing genes would impact mutant EGFR stability in NSCLC cancer cells. This massive and unbiased screening process successfully pinpointed a cell surface receptor, P2Y2, as an EGFR stabiliser.
To understand how P2Y2 stabilises EGFR, the team introduced a genetically encoded sensor to detect ATP, an energy-carrying molecule that powers cell activity. They saw that mutant EGFR forced cells to actively pump out more ATP, which in turn bound and activated P2Y2.
Digging deeper with mechanistic and functional studies, the researchers found that activated P2Y2 locked itself together with mutant EGFR and another protein, integrin β1, in a tightly bound protein complex. Mutant EGFR was scaffolded and surrounded by the other two proteins, shielding it from the cell’s disposal system for ordinary EGFR.
“We then demonstrated that when this positive feedback loop was disrupted—whether by breaking down ATP, or by chemically inhibiting or genetically removing P2Y2—physical levels of mutant EGFR protein dropped significantly in cells,” explained Boopathy. “This shift potential treatment strategies from simply blocking the protein’s activity to actively destroying it.”
Hong added that based on the team’s findings, NSCLC could be treated more effectively with a two-punch approach, combining EGFR-targeting drugs with P2Y2-targeting ones.
“By hitting the cancer from two different angles—blocking growth signals while simultaneously removing the scaffolding that keeps the mutant protein stable—we might be able to prevent resistance from developing in the first place,” said Boopathy.
Looking ahead, the team aims to identify or develop safe P2Y2 inhibitors. They will also explore whether a similar treatment strategy can be applied to other cancers which may also rely on stabilising proteins.
The A*STAR-affiliated researchers contributing to this research are from the A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB) and A*STAR Institute of Materials Research and Engineering (A*STAR IMRE).
