KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance.

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.

Hepatic Metastasis from Breast Cancer.

Breast cancer is the most common cancer in women and breast cancer liver metastasis may be associated with poor outcomes. Emerging locoregional therapies can be given in outpatient settings or with short hospital stays, to provide local control, support quality of life, preserve liver function, and potentially prolong survival. This review discusses retrospective studies suggesting potential benefits of locoregional treatment of breast cancer liver metastasis. Future prospective studies are needed to demonstrate efficacy and optimize patient selection.