The RTK-RAS-MAPK pathway is the most frequently altered signaling pathway at the rate of 46% across all cancer types. KRAS alternation is the top common event across all samples at 9%, and particularly predominant in pancreatic cancer (72%), colon cancer (69%) and lung cancer (33%). Oncogenic KRAS not only initiates tumorigenesis, but is also required for tumor maintenance, implying KRAS as an ideal therapeutic target for cancer treatment. Due to great advances of targeting RAS achieved in the past decade, KRAS can be druggable now by various methods. However, drug resistance occurs as expected, emphasizing that to overcome KRAS targeted therapy (KRASi) resistance is the key for favorable disease control.

Current projects focus on understanding tumor cell autonomous and non-autonomous KRASi resistance mechanisms, including exploring resistance-associated immune cells in the tumor microenvironment and dissecting how cell fate transition regulates KRASi resistance via epigenetic modulation.

Cells of the tumor microenvironment (TME) are plastic and mostly immune suppressive. Pancreatic cancer belongs to “cold tumor” with sparse cytotoxic immune cell infiltration. Thus, patients benefit little from current progress in immunotherapy. To change the scenario, our lab will exploit the hallmarks of pancreatic TME and take the advantage of our strength in cellular reprogramming to engineer myeloid cells. Our research goal is to rewire the TME from pro- to anti-tumor phenotype for achieving a durable disease control.

Current projects include developing chimeric antigen receptor (CAR) macrophage cell therapy and creating novel safety switches.