美国加州大学旧金山分校Marco Jost、Bhairavi Tolani等研究人员合作发现，在小鼠中Ras突变型癌症对V型ATP酶的小分子抑制作用敏感。相关论文于2022年7月25日在线发表在《自然—生物技术》杂志上。

Author: Tolani, Bhairavi, Celli, Anna, Yao, Yanmin, Tan, Yong Zi, Fetter, Richard, Liem, Christina R., de Smith, Adam J., Vasanthakumar, Thamiya, Bisignano, Paola, Cotton, Adam D., Seiple, Ian B., Rubinstein, John L., Jost, Marco, Weissman, Jonathan S.

Issue&Volume: 2022-07-25

Abstract: Mutations in Ras family proteins are implicated in 33% of human cancers, but direct pharmacological inhibition of Ras mutants remains challenging. As an alternative to direct inhibition, we screened for sensitivities in Ras-mutant cells and discovered 249C as a Ras-mutant selective cytotoxic agent with nanomolar potency against a spectrum of Ras-mutant cancers. 249C binds to vacuolar (V)-ATPase with nanomolar affinity and inhibits its activity, preventing lysosomal acidification and inhibiting autophagy and macropinocytosis pathways that several Ras-driven cancers rely on for survival. Unexpectedly, potency of 249C varies with the identity of the Ras driver mutation, with the highest potency for KRASG13D and G12V both in vitro and in vivo, highlighting a mutant-specific dependence on macropinocytosis and lysosomal pH. Indeed, 249C potently inhibits tumor growth without adverse side effects in mouse xenografts of KRAS-driven lung and colon cancers. A comparison of isogenic SW48 xenografts with different KRAS mutations confirmed that KRASG13D/+ (followed by G12V/+) mutations are especially sensitive to 249C treatment. These data establish proof-of-concept for targeting V-ATPase in cancers driven by specific KRAS mutations such as KRASG13D and G12V. Cancers with common KRAS mutations can be treated with an inhibitor of lysosomal acidification in mice.

DOI: 10.1038/s41587-022-01386-z

Source: https://www.nature.com/articles/s41587-022-01386-z