Pharmacological inhibition of the MVA pathway with statins effectively blocks KRAS localization to the cell membrane, overcoming KRASi resistance in CRC. Together, these findings identify epigenetic-metabolic coupling of cholesterol biosynthesis as a mechanism of KRASi resistance and highlight targetable metabolic vulnerability in KRAS-mutant CRC.

Using human and murine organoid models, we show that drug-induced inflammatory programs are, at least in part, cancer-cell autonomous, and precede the emergence of drug resistance. We identify TBK1 as a target to abrogate the inflammatory adaptive phase and enhance responses to KRAS inhibition.

P1, N=48, Not yet recruiting, Kumquat Biosciences Inc.

P1, N=101, Recruiting, Suzhou Abogen Biosciences Co., Ltd. | Not yet recruiting --> Recruiting

P1, N=210, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2033 --> Feb 2029 | Trial primary completion date: Jun 2031 --> Feb 2029

P1, N=210, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

P1/2, N=5, Completed, National Cancer Institute (NCI) | N=70 --> 5 | Recruiting --> Completed

P1, N=101, Not yet recruiting, Suzhou Abogen Biosciences Co., Ltd.

P1, N=237, Active, not recruiting, Quanta Therapeutics | Recruiting --> Active, not recruiting

P1, N=32, Not yet recruiting, Zhejiang Cancer Hospital; Shanghai Ruihongdi Pharmaceutical Co., LTD

P1, N=47, Completed, Boehringer Ingelheim | Active, not recruiting --> Completed

P1, N=188, Recruiting, Alterome Therapeutics, Inc. | N=130 --> 188