Some lung cancers manage to overcome a targeted drug therapy despite it showing initial success. Yale researchers have now discovered a molecular-level resistance mechanism that begins to take hold as early as six to eight weeks after the cancer drug is introduced. They reported their findings Oct. 23 in Nature Structural and Molecular Biology.
The study found that the protein METTL7A plays an important role early in the development of resistance to osimertinib, the frontline treatment for EGFR-mutant adenocarcinoma. The drug is a potent tyrosine kinase inhibitor (TKI) that blocks the epidermal growth factor receptor (EGFR) signaling pathway. That some patients eventually develop resistance poses a major obstacle to remission. Preventing resistance remains one of the central challenges for researchers and clinicians seeking more enduring results from these therapies.
The researchers found that METTL7A “primes” resistance, in part by remodeling chromatin, the structure that condenses and organizes DNA inside the nucleus. The altered DNA architecture then facilitates changes for gene amplification, leading to the proliferation of copies of cancer genes.
The researchers reasoned that blocking these initiating events may prevent resistance. They studied a short window of opportunity in TKI-resistant lung adenocarcinomas, between the start of drug therapy and the onset of gene amplification. When METTL7A was experimentally depleted before DNA structural reorganization was complete, cancer cells failed to develop resistance to the drug.
The discovery highlights METTL7A as a potential therapeutic target to block drug resistance at its source—not by targeting the amplified genes themselves, but by disrupting the chromatin reprogramming that enables them to form.
“Usually, we are reactive to cancer. With this discovery we have the potential to beat cancer at its own game,” says Andrew Xiao, PhD, senior author of the study, and an associate professor in the Department of Genetics at Yale School of Medicine. “METTL7A helps create a shortcut to gene amplification to overpower the therapy. Depleting METTL7A and interrupting its function early in the process, is putting up a wall to block cancer’s shortcut.”
Because gene amplification is a common resistance mechanism across cancers, the researchers conclude that these findings could extend beyond lung adenocarcinoma to additional therapy models that target different cancer mutations. The approach could offer a more efficient route than developing targeted drugs for each cancer.