decode KRAS targeted therapy resistance

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 (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 resistance (KTR) is the key for favorable disease control.

Our lab focuses on molecular understanding of tumor cell autonomous and non-autonomous KTR mechanisms, and rewiring tumor microenvironment (TME) from pro- to anti-resistance phenotype. Current projects include (1) identify KTR-associated cells of the TME, (2) delineate epigenetic mechanisms how cell fate transition regulates KTR, (3) demonstrate the role of metabolic pathways in regulating KTR, and (4) engineer tumor-associated immune cells to prevent KTR.

The long-term research goal of our lab is to discover novel and effective combinatorial strategies to thwart KRAS*-addicted cancers and prevent relapse by leveraging tumor intrinsic and extrinsic vulnerabilities.

Develop novel cell therapies

Cells of 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.