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Colorectal cancer (CRC) is a heterogeneous disease with a myriad of alterations at the cellular and molecular levels. Kristen rat sarcoma (KRAS) mutations occur in up to 40% of CRCs and serve as both a prognostic and predictive biomarker. Oncogenic mutations in the KRAS protein affect cellular proliferation and survival, leading to tumorigenesis through RAS/MAPK pathways. Until recently, only indirect targeting of the pathway had been investigated. There are now several KRAS allele-specific inhibitors in late-phase clinical trials, and many newer agents and targeting strategies undergoing preclinical and early-phase clinical testing. The adequate treatment of KRAS-mutated CRC will inevitably involve combination therapies due to the existence of robust adaptive resistance mechanisms in these tumors. In this article, we review the most recent understanding and findings related to targeting KRAS mutations in CRC, mechanisms of resistance to KRAS inhibitors, as well as evolving treatment strategies for KRAS-mutated CRC patients. [ABSTRACT FROM AUTHOR]

Lichens produce a large variety of secondary metabolites with diverse bioactivities, chemical structures, and physicochemical properties. For this reason, there is a growing interest in the use of lichen-derived bioactive molecules for drug discovery and development. Here, we report on the isolation, identification, and cytotoxic evaluation of gyrophoric acid (GA) from the lichen Umbilicaria muhlenbergii, a largely unexplored and scantly described lichen species. A simple purification protocol was developed for the fractionation of lichen crude extracts with silica gel column chromatography using solvents with changing polarity. GA was identified in one of the fractions with Fourier transform infrared spectroscopy (FTIR), ion trap mass spectrometry (MS), and nuclear magnetic resonance spectroscopy (1H-NMR and 13C-NMR). The FTIR spectra demonstrated the presence of aromatic and ester functional groups C=C, C-H, and C=O bonds, with the most remarkable signals recorded at 1400 cm−1 for the aromatic region, at 1400 cm−1 for the CH3 groups, and at 1650 cm−1 for the carbonyl groups in GA. The MS spectra showed a molecular ion [M-1]− at (m/z) 467 with a molecular weight of 468.4 and the molecular formula C24H20O10. that correspond to GA. The 1H-NMR and 13C-NMR spectra verified the chemical shifts that are typical for GA. GA reduced the cell viability of breast cancer cells from the MCF-7 cell line by 98%, which is indicative of the strong cytotoxic properties of GA and its significant potential to serve as a potent anticancer drug. [ABSTRACT FROM AUTHOR]