Targeting KRAS in cancer
Cet article passe en revue les mécanismes de régulation de KRAS ainsi que les résultats des essais cliniques d'inhibiteurs de KRAS G12C pour certains types de cancer, identifie les mécanismes de résistance à ces inhibiteurs ainsi que les combinaisons thérapeutiques permettant de lever cette résistance puis présente des approches immunothérapeutiques ciblant RAS ainsi que les futurs axes de recherche
RAS family variants—most of which involve KRAS—are the most commonly occurring hotspot mutations in human cancers and are associated with a poor prognosis. For almost four decades, KRAS has been considered undruggable, in part due to its structure, which lacks small-molecule binding sites. But recent developments in bioengineering, organic chemistry and related fields have provided the infrastructure to make direct KRAS targeting possible. The first successes occurred with allele-specific targeting of KRAS p.Gly12Cys (G12C) in non-small cell lung cancer, resulting in regulatory approval of two agents—sotorasib and adagrasib. Inhibitors targeting other variants beyond G12C have shown preliminary antitumor activity in highly refractory malignancies such as pancreatic cancer. Herein, we outline RAS pathobiology with a focus on KRAS, illustrate therapeutic approaches across a variety of malignancies, including emphasis on the ‘on’ and ‘off’ switch allele-specific and ‘pan’ RAS inhibitors, and review immunotherapeutic and other key combination RAS targeting strategies. We summarize mechanistic understanding of de novo and acquired resistance, review combination approaches, emerging technologies and drug development paradigms and outline a blueprint for the future of KRAS therapeutics with anticipated profound clinical impact.
Nature Medicine , résumé, 2024