"Undruggable KRAS": druggable after all.

The three <em>RAS</em> genes (<em>HRAS</em>, <em>KRAS</em>, and <em>NRAS</em>) comprise the most frequently mutated oncogene family in cancer. <em>KRAS</em> is the predominant isoform mutated in cancer and is most prevalently mutated in major causes of cancer deaths including lung, colorectal, and pancreatic cancers. Despite extensive academic and industry efforts to target KRAS, it would take nearly four decades before approval of the first clinically effective KRAS inhibitors for the treatment of KRAS mutant lung cancer. We revisit past anti-KRAS strategies and painful lessons learned and then focus on the rapidly evolving landscape of direct RAS inhibitors, resistance mechanisms, and potential combination treatments.