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.

Insulin-like growth factor 2 mRNA-binding protein 2 (IMP2) is an RNA-binding protein that positively regulates m6A-modified RNAs involved in critical cellular processes such as metabolism, oncogenesis, and immune function. Here, we elucidate facets of IMP2 biology, including several mechanisms of action on RNA, factors that regulate IMP2 expression, its relevant biological target RNAs, its role in normal development and disease, and its potential as a therapeutic target. IMP2 is a multi-level regulator of metabolism, influencing pathways linked to diabetes, obesity, and adipose function. Through genomic amplification and transcriptional overexpression in cancer cells, IMP2 can drive the initiation and progression of multiple cancer types, and high expression is associated with decreased overall survival of patients with cancer. IMP2 influences normal immune function, inflammation, macrophage polarization, and tumor immune evasion. IMP2 has emerged as a promising therapeutic target, particularly for cancers and metabolic diseases.