KRAS is a small GTPase that is among the most commonly mutated oncogenes in cancer. Here, we discuss KRAS biology, therapeutic avenues to target it, and mechanisms of resistance that tumors employ in response to KRAS inhibition. Several strategies are under investigation for inhibiting oncogenic KRAS, including small molecule compounds targeting specific KRAS mutations, pan-KRAS inhibitors, PROTACs, siRNAs, PNAs, and mutant KRAS-specific immunostimulatory strategies. A central challenge to therapeutic effectiveness is the frequent development of resistance to these treatments. Direct resistance mechanisms can involve KRAS mutations that reduce drug efficacy or copy number alterations that increase the expression of mutant KRAS. Indirect resistance mechanisms arise from mutations that can rescue mutant KRAS-dependent cells either by reactivating the same signaling or via alternative pathways. Further, non-mutational forms of resistance can take the form of epigenetic marks, transcriptional reprogramming, or alterations within the tumor microenvironment. As the possible strategies to inhibit KRAS expand, understanding the nuances of resistance mechanisms is paramount to the development of both enhanced therapeutics and innovative drug combinations.

A novel series of cannabichromene-derived amine and amide analogues (4−13) was synthesized and evaluated for their anticancer activity against the NCI-60 human tumor cell line panel. Among the synthesized derivatives, compounds 8 and 9 demonstrated the most potent and broad-spectrum anticancer activities, exhibiting significant percent growth inhibition across multiple cancer subtypes. Notably, compound 9 displayed good potency in prostate cancer cell lines PC-3 and DU-145, with GI50 values of 2.01 μM and 1.86 μM, respectively and pronounced cytotoxicity at higher concentrations. Its consistent performance across diverse cancer panels suggests a non-selective yet potent mechanism, likely targeting essential cellular pathways common to malignant cells. Compound 9 was found to induce apoptosis in PC-3 and DU-145 cells. Collectively, these findings highlight 9 as a promising compound for further optimization and mechanistic exploration towards developing new anticancer leads derived from the cannabichromene scaffold.