Year: 2017
Type: preprint
Abstract: The high prevalence of KRAS mutations in human cancers and the lack of effective treatments for patients ranks KRAS among the most highly sought-after targets for preclinical oncologists.Pharmaceutical companies and academic laboratories have tried for decades to identify small molecule inhibitors of oncogenic KRAS proteins, but little progress has been made and many have labeled KRAS undruggable.However, recent progress in in silico screening, fragmentbased drug design, disulfide tethered screening, and some emerging themes in RAS biology have caused the field to reconsider previously held notions about targeting KRAS.This review will cover some of the historical efforts to identify RAS inhibitors, and some of the most promising efforts currently being pursued.T he age of whole-genome sequencing has paved the road for "personalized" medicine in oncology.The Cancer Genome Atlas Research Network (2017), the Cancer Cell Line Encyclopedia (Barretina et al. 2012), the Genomics of Drug Sensitivity in Cancer (Yang et al. 2013), and similar efforts aim to catalog driver mutations with actionable and effective treatment regimens.While significant progress has been made in some notable areas, including BRAF-mutated melanomas (Davies et al. 2002;Chapman et al. 2011) and BRCA-mutated breast and ovarian cancers (Fong et al. 2009; The Cancer Genome Atlas Research Network 2011), many of the most common oncogenes were identified decades ago and remain the most deadly and elusive oncology drug targets.Perhaps chief among these is KRAS.Interest in KRAS as a cancer target stems from work with rodent sarcoma viruses in the late 1970s.First, DNAs from viruses and later from human tumor cells were shown to be sufficient to transform NIH-3T3 cells in culture (Shih et al. 1979;Shih et al. 1981).It was not until the early 1980s that KRAS was identified as the causative oncogene (Der et al. 1982;Parada and Weinberg 1983).By 1987, KRAS oncogenes were cloned from multiple tumor biopsies of lung, colon, and pancreas cancers (Santos et al. 1984;Bos et al. 1987;Forrester et al. 1987;Rodenhuis et al. 1987;Almoguera et al. 1988).By this time, all three RAS isoforms, H-, N-, and K-RAS were known and mutations at codons 12, 13, and 61 of a RAS isoform were shown to be sufficient to induce cell-cycle progression.Finally, the HRAS crystal structure revealed that the cancerassociated mutations at codons G12, G13, and Q61 are each located at a site of guanosine triphosphate (GTP) binding, suggesting a common mechanism of oncogenesis (Pai et al. 1989).
Author: Matthew Holderfield
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2766621097