Blocking proteins that cause cancer cells to mutate and resist treatment could significantly improve outcomes for some patients with non-small cell lung cancer (NSCLC), the most common type of lung cancer, according to a new Yale study.
The study, led by Yale School of Public Health (YSPH) professor Dr. Jeffrey Townsend, PhD, found that suppressing the enzyme family known as APOBEC could dramatically delay the emergence of resistance in many lung cancer patients undergoing tyrosine kinase inhibitor (TKI) therapy. The findings pave the way for more personalized and durable treatment strategies for a disease that remains one of the deadliest forms of cancer worldwide.
“Our research shows that by suppressing APOBEC-driven mutagenesis, we can significantly extend the window before cancer develops resistance to targeted therapies,” said Townsend, Elihu Professor of Biostatistics at YSPH and professor of ecology and evolutionary biology at Yale. “But the benefits aren’t uniform—some patients stand to gain much more than others. Precision medicine approaches are essential.”
Townsend is co-leader of the Genomics, Genetics & Epigenetics Research Program at Yale Cancer Center (YCC). He also serves as co-chair of the Cancer Evolution Working Group of the American Association for Cancer Research.
Our analysis quantifies how much time could be gained for each patient, based on their tumor molecular profile.
Dr. Jeffrey Townsend, Yale School of Public Health
APOBEC’s Hidden Role in Cancer Resistance
Non-small cell lung cancer patients often receive TKI therapy to inhibit specific molecular drivers of tumor growth. However, these therapies frequently lose effectiveness over time as tumors acquire new mutations that render the drugs useless. Previous research has suggested that TKI treatment itself can trigger APOBEC enzymes, which induce mutations in tumor DNA that, in turn, confer drug resistance.
To investigate this phenomenon, the research team analyzed tumor genetic sequencing data from 21 NSCLC patients who had undergone TKI therapy. Using advanced data-driven computational models, the team then measured how much APOBEC-induced mutations contributed to resistance in each case.
Besides Townsend, the research team included experts from the YSPH Department of Biostatistics and Yale’s Program in Computational Biology and Biomedical Informatics, as well as scientists from YCC and Yale’s Department of Pharmacology.
Their findings showed wide variability: in some tumors, APOBEC activity played a major role in producing resistance mutations, while in others, it was minimal. Tumors driven by Anaplastic Lymphoma Kinase (ALK) rearrangements were especially prone to APOBEC-mediated mutations, compared to tumors with Epidermal Growth Factor Receptor (EGFR) mutations.
“ALK-positive lung cancers, in particular, appear to be more vulnerable to this process,” Townsend said. “Patients with ALK-driven tumors could benefit the most from early intervention with APOBEC inhibitors.”
A Personalized Approach to Extending Lung Cancer Survival
The researchers projected how much longer TKI therapy could remain effective if APOBEC activity were fully suppressed. In the most responsive patients, they estimated potential delays in resistance emergence of over 1200%, translating into phenomenal extensions in progression-free survival.
However, for patients whose resistance mutations were not strongly driven by APOBEC, inhibiting the enzymes would offer little or no advantage. Thus, precision diagnostics to identify which patients are most likely to benefit from APOBEC-targeted interventions is vital, the researchers said.
“Our analysis quantifies how much time could be gained for each patient, based on their tumor molecular profile,” Townsend explained. “It’s a step toward more tailored, evidence-driven decisions about combination therapies.”
Future of APOBEC Inhibitors
APOBEC inhibitors are not yet available clinically. However, recent advances in drug development—particularly the creation of small-molecule inhibitors that block APOBEC3A activity—have generated optimism about future drug availability. The study’s findings provide a strong rationale for incorporating precision APOBEC suppression strategies into clinical trials for NSCLC and other cancers where APOBEC plays a role.
The team also stressed the importance of early intervention. Since APOBEC activity can escalate during therapy, catching and suppressing it early could prevent the accumulation of mutations that eventually lead to drug failure.
“We see a clear window of opportunity,” Townsend said. “If you can inhibit APOBEC activity before resistant clones even appear, you might significantly delay treatment failure and give patients more time with effective therapy.”
A Path Forward for Precision Medicine
The study highlights the Yale School of Public Health’s leadership in the study of disease evolution. By understanding how tumors mutate and evolve under therapy-induced stress, researchers and clinicians can design smarter strategies to outmaneuver cancer.
“This work is an example of the power obtained by applying evolutionary biology to medicine,” Townsend noted. “Instead of reacting to resistance after it happens, we’re identifying ways to proactively slow down the evolutionary process itself.”
The study, published in the journal Lung Cancer, was funded by the National Institutes of Health.
Orestis Nousias is the study’s lead author. PhD student Jeffrey D. Mandell is a co-author. Both are affiliated with the YSPH Department of Biostatistics. Dr. Karen S. Anderson, PhD, a professor of pharmacology and of molecular biophysics and biochemistry at Yale, is also a co-author. Dr. Anderson is also affiliated with YCC.
Artificial intelligence software assisted in the creation of this article.