Abstract:RAS proteins are binary switches, cycling between ON and OFF states during signal transduction. These switches are normally tightly controlled, but in RAS-related diseases, such as cancer, RASopathies, and many psychiatric disorders, mutations in the RAS genes or their regulators render RAS proteins persistently active. The structural basis of the switch and many of the pathways that RAS controls are well known, but the precise mechanisms by which RAS proteins function are less clear. All RAS biology occurs in… Show more
“…KRAS is one of the most frequently mutated oncogenes in cancer42 but is only rarely mutated in HCC 14. Therefore, the expression and function of KRAS in HCC were widely unexplored.…”
KRAS is dysregulated in HCC by loss of tumour-suppressive microRNA-622, contributing to tumour progression, sorafenib sensitivity and resistance. KRAS inhibition alone or in combination with sorafenib appears as novel promising therapeutic strategy for HCC.
“…KRAS is one of the most frequently mutated oncogenes in cancer42 but is only rarely mutated in HCC 14. Therefore, the expression and function of KRAS in HCC were widely unexplored.…”
KRAS is dysregulated in HCC by loss of tumour-suppressive microRNA-622, contributing to tumour progression, sorafenib sensitivity and resistance. KRAS inhibition alone or in combination with sorafenib appears as novel promising therapeutic strategy for HCC.
“…The Rat sarcoma ( RAS ) oncogene family is comprised of three members ( KRAS , HRAS , and NRAS ) that play an important role in human cancer [1]. All RAS genes encode 21 kD monomeric GTPases that function to transduce extracellular signals to intracellular signal transduction cascades.…”
Section: K-ras Is An Oncogenic Gtpasementioning
confidence: 99%
“…Missense mutations in RAS proteins alter the homeostatic balance of GDP and GTP binding toward the active state, either by reducing GTP hydrolysis or by increasing the rate of GTP loading. There has been considerable work over the past several decades comparing mutant and wild-type (WT) forms of RAS [1, 2], with relatively little attention paid to potential differences between the specific mutations that give rise to the activated oncoproteins. This review explores the broad array of evidence for functionally distinct allelic forms of RAS.…”
KRAS is the most frequently mutated oncogene in cancer and KRAS mutation is commonly associated with poor prognosis and resistance to therapy. Since the KRAS oncoprotein is, as yet, not directly druggable, efforts to target KRAS mutant cancers focus on identifying vulnerabilities in downstream signaling pathway or in stress-response pathways that are permissive for strong oncogenic signaling. One aspect of KRAS biology that is not well appreciated is the potential biological differences between the many distinct KRAS activating mutations. This review draws upon insights from both clinical and experimental studies to explore similarities and differences among KRAS alleles. Historical and emerging evidence supports the notion that the specific biology related to each allele might be exploitable for allele-specific therapy.
“…This hypothesis is particularly attractive in view of the frequency of RAS gene mutations in human cancers and the difficulties of targeting mutant RAS proteins [47][48][49] . Because DUSP6 directly controls the activities of ERK1…”
We recently described the synthetic lethality that results when mutant KRAS and mutant EGFR are coexpressed in human lung adenocarcinoma (LUAD) cells, revealing the biological basis for the mutual exclusivity of KRAS and EGFR mutations in lung cancers. We have now further defined the biochemical events responsible for the toxic effects of signaling through the RAS pathway. By combining pharmacological and genetic approaches, we have developed multiple lines of evidence that signaling through extracellular signalregulated kinases (ERK1/2) mediates the toxicity. These findings imply that tumors with mutant oncogenes that drive signaling through the RAS pathway must restrain the activity of ERK1/2 to avoid cell toxicities and enable tumor growth. In particular, a dual specificity phosphatase, DUSP6, regulates phosphorylated (P)-ERK levels in lung adenocarcinoma cells, providing negative feedback to the RAS signaling pathway. Accordingly, inhibition of DUSP6 is cytotoxic in LUAD cells driven by either mutant KRAS or mutant EGFR, phenocopying the effects of co-expression of mutant KRAS and EGFR. Together, these data suggest that targeting DUSP6 or other feedback regulators of the EGFR-KRAS-ERK pathway may offer a strategy for treating certain cancers by exceeding an upper threshold of RAS-mediated signaling.
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