Synthetic lethality: emerging targets and opportunities in melanoma

Thompson, Nicola; Adams, David J.; Ranzani, Marco

doi:10.1111/pcmr.12573

Cited by 14 publications

(11 citation statements)

References 126 publications

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“…Indeed, prior evidence of manipulating autophagy by inhibiting ICMT has shown encouraging results [300][301][302], which supports that ICMT can be used to regulate RAS-driven signaling. For the effort of identifying the targets downstream of ERK signaling in modulating autophagy, several screens have been carried out with whole genome shRNA knockdown libraries, which yielded few druggable factors [303]. The strong biology, however, appeals to future reliable screening approaches such as Cas9-CRISPR-mediated knockout [304].…”

Section: Is Ras Druggable?mentioning

confidence: 99%

Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy

Degirmenci

Wang

2020

Cells

400

303

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The RAS/RAF/MEK/ERK (MAPK) signaling cascade is essential for cell inter- and intra-cellular communication, which regulates fundamental cell functions such as growth, survival, and differentiation. The MAPK pathway also integrates signals from complex intracellular networks in performing cellular functions. Despite the initial discovery of the core elements of the MAPK pathways nearly four decades ago, additional findings continue to make a thorough understanding of the molecular mechanisms involved in the regulation of this pathway challenging. Considerable effort has been focused on the regulation of RAF, especially after the discovery of drug resistance and paradoxical activation upon inhibitor binding to the kinase. RAF activity is regulated by phosphorylation and conformation-dependent regulation, including auto-inhibition and dimerization. In this review, we summarize the recent major findings in the study of the RAS/RAF/MEK/ERK signaling cascade, particularly with respect to the impact on clinical cancer therapy.

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Section: Is Ras Druggable?mentioning

confidence: 99%

Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy

Degirmenci

Wang

2020

Cells

400

303

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“…The development of novel cancer drugs is a time-consuming and expensive process with a high rate of failure in late-stage clinical trials (58). The synthetic lethality strategy to identify novel partners for potential genetic mutations has emerged to overcome this challenge (5,8). Homologous recombination deficiency including BRCA1/2 or p53 mutations combined with an increase in replication stress may result in a tumor being more susceptible to PARP inhibition (38,45,49,56).…”

Section: Discussionmentioning

confidence: 99%

“…Substantial progress has been made in the treatment of ovarian cancer through use of targeted therapies and immunotherapy (5). Anti-angiogenic therapy using bevacizumab, considered the most promising targeted therapy for ovarian cancer, may improve the overall survival time of patients with poor prognosis (6).…”

Section: Introductionmentioning

confidence: 99%

Conceptual frameworks of synthetic lethality in clear cell carcinoma of the ovary (Review)

et al. 2018

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Abstract. Targeting non-oncogenes may result in the selective death of cancer cells. Clear cell carcinoma of the ovary (CCC) may exhibit resistance against conventional chemotherapy and is associated with poor prognosis. The aim of the present report was to review synthetic lethality-based therapies for CCC. Previous English-language studies were reviewed to accumulate preclinical and clinical data on targeting synthetic lethal partners. Synthetic lethal interactions have a variety of types, involving components of a backup or parallel pathway with overlapping functions, components encoded by paralogous pairs, subunit components that form heteromeric complexes and components that are arranged in a single linear pathway. A set of candidate gene targets potentially resulting in synthetic lethality have been previously identified. HNF class homeobox, AT-rich interaction domain 1A, ATR serine/threonine kinase, ATM serine/threonine kinase, checkpoint kinase 1 and phosphatase and tensin homolog may be the key partner genes. A variety of loss of function genes in CCC are driver or passenger events and may function as synthetic lethal pairs under replication stress conditions. Further clinical studies will be required to investigate the safety and therapeutic effect of synthetic lethality pairs in CCC tumor types with replication stress.

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“…There may be different causes of the synthetic lethality such as mutation, epigenetic alterations or suppression of any gene (Lord et al, 2015). Synthetic lethality is used for the purpose of molecular targeted therapy for cancer (Thompson et al, 2017). In 2016, FDA approved inactivated tumor suppressor gene (BRCA1 and BRCA2) as the first example of a molecular targeted therapy exploiting the synthetic lethality (Lord and Ashworth, 2013).…”

Section: Synthetic Lethalitymentioning

confidence: 99%

Toxicity of anticancer drugs and its prevention with special reference to role of garlic constituents

Raisuddin¹,

Ahmad²,

Fatima³

et al. 2018

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Cancer is the leading cause of death globally. World Health Organisation (WHO) reported that 70% of death caused by cancer occurs in low or middle income countries which may be due to unavailability of correct treatment or delayed medical support. Despite of different therapies available to cure the cancer or to prolong the life of cancer survivors; chemotherapy is still central to cancer therapy. Administration of chemotherapeutic drugs either independently or in combination with other therapies such as irradiation or surgery provides relief to cancer patients. Nitrogen mustards were the first anticancer agents used in chemotherapy in 1940s. Their clinical use accelerated the development of different anticancers drugs. Due to the reports of toxicities of these anticancer drugs, herbal remedies for cancer treatment found notion of oncologists. A number of herbal extracts and natural products have shown the potential of anticancer activity. They also reduce the toxicity of synthetic anticancer drugs. Garlic (Allium sativum L.) is one of the herbal remedies with high anticancer potentia l and ability to mitigate the toxicities of anticancer drugs. The protective effects of garlic against the toxicities of anticancer drugs have been reported in a number of studies and it has also been reported that fresh garlic and aged garlic extra ct show considerable protective effects. Allicin (diallyl thiosulfinate) is the major pharmacological component of garlic which has attracted attention of the international medical field gradually due to its potential for disease prevention and trea tment. The major unique organosulfur compounds in aged garlic extract such as water-soluble S-allyl cysteine (SAC) and Sallylmercaptocysteine (SAMC) have potent antioxidant activity. Many reports show the protective potential of these garlic constituents against anticancer drug-induced toxicities. Here, we present review of toxicities caused by anticancer drugs and their mechanism of action along with the efficacy of some plant extracts and natural products in reducing toxicity of anticancer drugs with special reference to of garlic constituents.

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Synthetic lethality: emerging targets and opportunities in melanoma

Cited by 14 publications

References 126 publications

Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy

Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy

Conceptual frameworks of synthetic lethality in clear cell carcinoma of the ovary (Review)

Toxicity of anticancer drugs and its prevention with special reference to role of garlic constituents

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