Drugging ‘undruggable’ RAS for cancer treatment: mission possible?
Lineberger Comprehensive Cancer Center / University of North Carolina (NC, USA)
Despite being the very first cancer genes identified in 1982, despite nearly four decades of intensive efforts in academia and the pharmaceutical industry, no effective therapies have reached the clinic for the treatment of RAS-mutant cancers. However, recent significant progress has been made where there is now cautious hope that this holy grail of cancer research may finally be achieved. In this presentation, I will describe our efforts to develop anti-RAS therapies. Our research centers on pancreatic ductal adenocarcinoma (PDAC), where the frequency of KRAS mutations is ~95%, and consequently, is considered the most RAS-addicted cancer. One major focus of our research is the RAF-MEK-ERK mitogen-activated protein kinase cascade. I will describe our efforts to target this kinase cascade, including studies that have led to our initiation of clinical trials targeting the metabolic processes of autophagy, macropinocytosis and mitochondrial function. Another major area of study involves inhibitors that directly target mutant KRAS, in particular the KRASG12C mutation. Although early clinical results support the promise of G12C inhibitors, treatment-induced cancer cell resistance will likely limit their long-term effectiveness. Therefore, combination approaches will need to be identified. I will describe our studies to achieve this goal.