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Semin Cancer Biol. 2019 Feb;54:80-90. doi: 10.1016/j.semcancer.2018.01.016. Epub 2018 Feb 9.

Targeting the RAS-dependent chemoresistance: The Warburg connection.

Author information

1
Translational Oncology Division, Oncohealth Institute, Fundacion Jimenez Diaz University Hospital, 28040, Madrid, Spain.
2
Translational Oncology Division, Oncohealth Institute, Fundacion Jimenez Diaz University Hospital, 28040, Madrid, Spain. Electronic address: oscar.aguilera@FJD.es.

Abstract

RAS protein family members (KRAS4A, KRAS4B, HRAS and NRAS) function as GDP-GTP-regulated on-off switches, which regulate cytoplasmic-nuclear signaling networks ruling diverse normal cellular processes. Constitutive activating mutations in RAS genes are found in up to 30% of human cancers, and remarkably, the oncogenic Ras mutations and mutations in other components of Ras/MAPK signaling pathways seem to be mutually exclusive in most tumors, pointing out that deregulation of Ras-dependent signaling is an essential requirement for tumorigenesis. Up to 30% of solid tumors are known to have a mutated (abnormal) KRAS gene. Unfortunately, patients harboring mutated KRAS CRC are unlikely to benefit from anti-EGFR therapy. Moreover, it remains unclear that patients with KRAS wild-type CRC will definitely respond to such therapies. Although some clinically designed-strategies to modulate KRAS aberrant activation have been designed, all attempts to target KRAS have failed in the clinical assays and K-RAS has been assumed to be invulnerable to chemotherapeutic attack. Recently, different encouraging publications reported that ascorbate may have a selective antitumoral effect on KRAS mutant cancer cells. In this review we aim to describe the prevalence and importance of KRAS mutation in cancer and associated problems for the clinical handling of patients harboring these tumors. We highlight the role of mutated KRAS in boosting and keeping the tumor associated aberrant cell metabolism stating that further in-depth studies on the molecular mechanism of ascorbate to bypass mutated KRAS-related metabolic alterations may constitute a new pathway to design novel molecules in order handle tumor resistance to anti EGFR-therapies.

KEYWORDS:

Cancer; Chemoresistance; Kras; Metabolism; Vitamin C

PMID:
29432815
DOI:
10.1016/j.semcancer.2018.01.016
[Indexed for MEDLINE]

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