New Strategies Generate Optimism for Targeting "Undruggable" KRAS

Jane De Lartigue, PhD
Published: Wednesday, Oct 09, 2019
Vassiliki Papadimitrakopoulou, MD, chief, Section of Thoracic Medical Oncology, the University of Texas MD Anderson Cancer Center

Vassiliki Papadimitrakopoulou, MD

After 30 years of frustration, investigators are starting to make headway in their quest to develop therapies that counteract oncogenic mutations in the KRAS gene, a high-priority target in precision medicine that has long been deemed “undruggable.”1-3

The discovery of binding pockets on a mutant form of the KRAS protein encoded by KRAS G12C has facilitated the development of novel mutant-specific inhibitors that are showing promise.4-6

In June, data demonstrating that AMG 510, a small-molecule inhibitor of KRAS G12C, elicited objective responses in patients with KRAS-mutant non–small cell lung cancer (NSCLC) generated much excitement at the American Society of Clinical Oncology Annual Meeting (ASCO 2019). Amgen, the company developing the drug, subsequently said the agent has also induced responses in colorectal (CRC) and appendiceal cancers.7,8

Meanwhile, there is renewed hope for exploring other nodes of the KRAS cell signaling network, which includes the downstream MEK cascade, potentially allowing for additional strategies (Figure).3,9 Investigators are pursuing a variety of direct and indirect approaches to address mutant KRAS activity, including potential synergy with combination targeted therapies and PD-1 inhibition (Table).

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