Undruggable KRAS—time to rebrand?

After decades of research into KRAS-mutant cancers, clinical development drugs targeting this pervasive mutation is finally showing some much-awaited promise. RAS proteins are a family prototypical oncogenes that mutated in many human cancers. KRAS the most frequently isoform mutations (86%), and 90% pancreatic 40% colorectal 30% lung Cancers with these associated poor treatment responses prognosis. Mutant has long been referred to as an undruggable target because its unusual shape. Compared other proteins, relatively smooth protein structure meant designing inhibitors bind surface grooves was difficult, stalling progress drug for years. But, major breakthrough 2013, compound developed could small pocket mutant Gly12Cys protein, reinvigorating efforts find active inhibitor. Development were selective forms also reduced toxicity might have observed widescale inhibition ubiquitous protein. Although recently still failed late-stage trials (eg, AZD4785), advance 2013 led new reaching further stages development, recent data representing first phase 2 evidence activity At World Conference on Lung Cancer held virtually Jan 28–31, 2021, results from CodeBreak 100 trial presented. In single-arm study, 124 patients previously treated non-small-cell cancer (NSCLC) centrally confirmed enrolled given sotorasib, which targets mutation. 46 (37%) had overall response (including two complete responses), median progression-free survival 6·8 months. The clinically meaningful preliminary 1 part 3 study planned (NCT04303780). late 2020, another inhibitor mutation—adagrasib—also showed antitumour subset NSCLC. KRYSTAL-1 presented at EORTC-NCI-AACR Symposium Molecular Targets Therapeutics October, 79 NSCLC adagrasib twice day, resulting objective 23 (45%) 51 evaluable patients—another encouraging result high unmet need. view previous, unsuccessful attempts cancer, fact included already received previous lines therapy, sign barriers surmountable. However, early results. registrational and, together KRYSTAL-1, outlook good, but confirmatory studies larger patient populations comparison current standard care needed. Moreover, although being made not striking. only three (17%) 18 or solid tumours response. An need remains, different approaches required. highly prevalent, potentially targetable, mutations, such Gly12Asp, prevalent types. Use pan-KRAS block irrespective type, BBP-454 (in preclinical phase), open up broader populations, safety approach will be important consideration. Another concept explored use combination therapies. For example, initiated test blockade immune checkpoint With dismal success rate past 30 years, deemed impossible too long. New results, goal improving outcomes difficult-to-treat seems more like possibility than mere pipe dream. Research area gaining momentum. On wave renewed enthusiasm rare story hope discovery, label now unsuitable unhopeful, therapies deadly cancers within our grasp.