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Non-Redundant and Overlapping Oncogenic Readouts of Non-Canonical and Novel Colorectal Cancer KRAS and NRAS Mutants

1
Disease Molecular Biology and Epigenetics Laboratory, National Institute of Molecular Biology and Biotechnology, University of the Philippines Diliman, Quezon City 1101, Philippines
2
Institute of Human Genetics, National Institutes of Health, University of the Philippines Manila, Manila 1000, Philippines
3
Philippine Genome Center, University of the Philippines System, Quezon City 1101, Philippines
*
Author to whom correspondence should be addressed.
Present Address: Center for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA.
Present Address: Division of B Cell Immunology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
§
These authors contributed equally to this work.
Present Address: Division of Cancer Genome Research, German Cancer Research Center and National Center for Tumor Diseases, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
Cells 2019, 8(12), 1557; https://doi.org/10.3390/cells8121557
Received: 3 November 2019 / Revised: 27 November 2019 / Accepted: 27 November 2019 / Published: 3 December 2019
(This article belongs to the Special Issue Role of KRAS in Colorectal Cancer)
RAS oncogene family members are molecular switches of signaling pathways that control cell growth, proliferation, differentiation, and survival. In colorectal cancer, Kirsten-RAS (KRAS) and neuroblastoma-RAS (NRAS) are the commonly mutated isoforms. Activating mutations in RAS result in cellular transformation independent of upregulated epidermal growth factor receptor (EGFR)-initiated signaling. The present study characterized the functional consequences of non-canonical/novel KRAS and NRAS mutants identified in a targeted next-generation sequencing study of colorectal cancer specimens from Filipino patients. In vitro assays in NIH3T3 cells showed that similar to the canonical KRAS G12D mutant, overexpression of KRAS G12S, A59T, and Y137C, but not NRAS G12D and NRAS A11V, confer higher proliferation and migration rates. HCT116 cells transfected with the novel NRAS A11V and the canonical NRAS G12D, but not the KRAS mutants, display enhanced resistance to apoptosis. All four non-canonical/novel KRAS and NRAS mutants induce gross changes in F-actin cytoskeletal organization and cellular morphology of NIH3T3 cells. Only KRAS G12S and KRAS A59T appear to deregulate extracellular signal-regulated kinase (ERK) and its downstream target ETS transcription factor ELK1 (ELK1). Elucidation of differential effector engagement responsible for the variable phenotypic readouts of the mutants is warranted. If validated by mouse studies and clinical correlates, these can have wider implications in choosing treatment options. View Full-Text
Keywords: KRAS; NRAS; colorectal cancer; carcinogenesis; epidermal growth factor receptor pathway KRAS; NRAS; colorectal cancer; carcinogenesis; epidermal growth factor receptor pathway
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MDPI and ACS Style

Alcantara, K.M.M.; Malapit, J.R.P.; Yu, R.T.D.; Garrido, J.A.M.G.; Rigor, J.P.T.; Angeles, A.K.J.; Cutiongco-de la Paz, E.M.; Garcia, R.L. Non-Redundant and Overlapping Oncogenic Readouts of Non-Canonical and Novel Colorectal Cancer KRAS and NRAS Mutants. Cells 2019, 8, 1557. https://doi.org/10.3390/cells8121557

AMA Style

Alcantara KMM, Malapit JRP, Yu RTD, Garrido JAMG, Rigor JPT, Angeles AKJ, Cutiongco-de la Paz EM, Garcia RL. Non-Redundant and Overlapping Oncogenic Readouts of Non-Canonical and Novel Colorectal Cancer KRAS and NRAS Mutants. Cells. 2019; 8(12):1557. https://doi.org/10.3390/cells8121557

Chicago/Turabian Style

Alcantara, Krizelle M.M., Joshua R.P. Malapit, Ryan T.D. Yu, Jose A.M.G. Garrido, John P.T. Rigor, Arlou K.J. Angeles, Eva M. Cutiongco-de la Paz, and Reynaldo L. Garcia 2019. "Non-Redundant and Overlapping Oncogenic Readouts of Non-Canonical and Novel Colorectal Cancer KRAS and NRAS Mutants" Cells 8, no. 12: 1557. https://doi.org/10.3390/cells8121557

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