Researchers at Duke-NUS School of Medicine have discovered a molecular “switch” that determines whether pancreatic cancer cells respond to or resist chemotherapy. The discovery points to a potential way to shift some of the most treatment-resistant tumors to a state where existing drugs can work more effectively.
This study clinical research journalLet’s explain how this switch works at a molecular level. The results suggest that combining targeted therapy with standard chemotherapy may improve outcomes for patients whose tumors no longer respond to treatment.
Why pancreatic cancer is so difficult to treat
Pancreatic cancer is one of the deadliest cancers worldwide. In Singapore, cancer is the ninth most common cancer but the fourth leading cause of cancer-related deaths. Because symptoms often appear late and current treatments have limited effectiveness, most patients rely on chemotherapy, which generally has only a modest effect.
Over the past decade, scientists have identified two major molecular subtypes of pancreatic cancer: classic cancer and basal cancer. Classic subtype tumors tend to be more organized at the cellular level, and patients with this form are more likely to respond to treatment. In contrast, tumors of the basal subtype are more disorganized, more aggressive, and often resistant to chemotherapy.
Importantly, pancreatic cancer cells are not fixed into one subtype. They can transition between these states, moving from more treatable forms to more resistant forms. This flexibility is known as cancer cell plasticity.
Role of GATA6 in tumor behavior
The research team focused on a gene called GATA6, which helps keep pancreatic cancer cells in their classic, more structured and less aggressive state. When GATA6 levels are high, tumors tend to grow more organically and are more likely to respond to chemotherapy. When GATA6 levels decrease, cells lose their structure and become more aggressive and difficult to treat.
Professor David Wilschap of Duke-NUS’ Cancer and Stem Cell Biology Program, lead author of the study, said:
“We know that pancreatic cancer cells can switch between these two states. What we didn’t understand was the mechanism driving that switch. By identifying the pathway that suppresses GATA6, we now have a clearer picture of how tumors become resistant and, potentially, how to reverse the process.”
KRAS and ERK pathways drive the switch
Researchers tracked the switch to a series of signals within pancreatic cancer cells. A gene called KRAS is mutated in nearly all pancreatic cancers and sends continuous growth signals that promote tumor development. KRAS passes these signals through partner proteins known as ERKs, which relay instructions further inside the cell.
When the ERK pathway is highly activated, it protects another protein that prevents the production of GATA6. When GATA6 levels decrease, cancer cells lose their organized structure, transition to a more aggressive ground state, and are significantly less responsive to chemotherapy.
Using genetic screening, molecular analysis of cancer cells, and drug treatment, the research team demonstrated that blocking the KRAS and ERK pathways relieves this suppression. If that happens, the level of GATA6 will rise again. The cancer cells then return to a more organized state and regain sensitivity to chemotherapy.
Combination therapy shows stronger effects
The study also found that higher levels of GATA6, by themselves, made pancreatic cancer cells more responsive to treatment. Combining drugs that inhibit the KRAS and ERK pathways with standard chemotherapy produced stronger anticancer effects than using either approach alone. However, this enhanced benefit only occurs in the presence of GATA6, highlighting its central role in determining which patients benefit most from combination therapy.
These findings help clarify why patients with high GATA6 levels respond better to certain chemotherapy regimens. It also provides a scientific foundation for ongoing clinical trials testing new treatments targeting KRAS and related pathways.
Professor Lok Sheemei, interim associate dean for research at Duke-NUS, said:
“Pancreatic cancer remains one of the most difficult cancers to treat. These findings explain the mechanisms of why tumors respond poorly to chemotherapy and provide a rational strategy to combine targeted therapies with existing drugs.”
Broad impact on other KRAS-induced cancers
The impact may extend beyond pancreatic cancer. Many other cancers caused by KRAS mutations show similar changes in cell behavior and treatment response. Understanding how cancer cells transition between different states could help researchers address treatment resistance in other types of cancer.
Professor Patrick Tan, Dean and Professor of Cancer and Stem Cell Biology at Duke-NUS commented:
“This study shows how basic science can reveal actionable insights into treatment resistance. Understanding how cancer cells switch states provides a more strategic way to design combination therapies.”
Duke-NUS Medical School is internationally recognized for its leadership in medical education and biomedical research, combining basic discovery and translational expertise to improve health outcomes in Singapore and beyond.
