Phase II trial of trametinib in combination with the AKT inhibitor GSK 2141795 in BRAF wild-type melanoma.

Algazi, Alain P.; Muthukumar, Adele H.; O’Brien, Kelly; Lencioni, Alex; Tsai, Katy K.; Kadafour, Maha; Chapman, Paul B.; Daud, Adil

doi:10.1200/jco.2015.33.15_suppl.9068

Cited by 12 publications

(11 citation statements)

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“…Afuresertib has also been tested in combination with a MEK inhibitor, trametinib with only intermittent dosing being tolerable (Tolcher et al, 2015b). Continuous dosing schedules of GSK214795 in combination with trametinib have been achieved (Algazi et al, 2015; Shoushtari et al, 2016) and a number of trials exploring GSK2141795 in combination with trametinib are ongoing (Table 2). Preclinical data has clearly demonstrated that sub-maximal inhibition of the combination of MEK and AKT does not significantly increase growth inhibition of BRAF or PIK3CA mutant cells, compared to maximally inhibiting MEK or AKT alone (Stewart et al, 2015).…”

Section: The Clinical Development Of Akt Inhibitorsmentioning

confidence: 99%

Maximising the potential of AKT inhibitors as anti-cancer treatments

Brown

Banerji

2017

Pharmacology & Therapeutics

190

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PI3K/AKT signalling is commonly disrupted in human cancers, with AKT being a central component of the pathway, influencing multiple processes that are directly involved in tumourigenesis. Targeting AKT is therefore a highly attractive anti-cancer strategy with multiple AKT inhibitors now in various stages of clinical development. In this review, we summarise the role and regulation of AKT signalling in normal cellular physiology. We highlight the mechanisms by which AKT signalling can be hyperactivated in cancers and discuss the past, present and future clinical strategies for AKT inhibition in oncology.

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Section: The Clinical Development Of Akt Inhibitorsmentioning

confidence: 99%

Maximising the potential of AKT inhibitors as anti-cancer treatments

Brown

Banerji

2017

Pharmacology & Therapeutics

190

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“…A phase I dose‐escalation study of GSK2141795 in combination with BRAF inhibition is ongoing in solid tumours, and phase II studies in acute myeloid leukaemia, multiple myeloma and triple negative breast cancer. Toxicities thus far include grade II–III skin rash and diarrhoea .…”

Section: Ongoing Clinical Trialsmentioning

confidence: 99%

AKT in cancer: new molecular insights and advances in drug development

Mundi

Sachdev

McCourt

et al. 2016

Brit J Clinical Pharma

211

189

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The phosphatidylinositol-3 kinase (PI3K)-AKT pathway is one of the most commonly dysregulated pathways in all of cancer, with somatic mutations, copy number alterations, aberrant epigenetic regulation and increased expression in a number of cancers. The carefully maintained homeostatic balance of cell division and growth on one hand, and programmed cell death on the other, is universally disturbed in tumorigenesis, and downstream effectors of the PI3K-AKT pathway play an important role in this disturbance. With a wide array of downstream effectors involved in cell survival and proliferation, the well-characterized direct interactions of AKT make it a highly attractive yet elusive target for cancer therapy. Here, we review the salient features of this pathway, evidence of its role in promoting tumorigenesis and recent progress in the development of therapeutic agents that target AKT.

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“…17,18 Unfortunately, recent studies suggested that targeting AKT signaling alone or in combination with MAPK is not clinically effective. 19,20,21 AZD5363, a new generation pan AKT inhibitor, although well tolerated, yielded a partial response in only 2 of the 92 patients with advanced solid tumors. 14 Co-treatment of MEK inhibitor, trametinib, with orally bioavailable pan Akt inhibitor, GSK2141795, led to stable disease in 65% of the melanoma patients, without any partial or complete responses.…”

Section: Introductionmentioning

confidence: 99%

“…14 Co-treatment of MEK inhibitor, trametinib, with orally bioavailable pan Akt inhibitor, GSK2141795, led to stable disease in 65% of the melanoma patients, without any partial or complete responses. 21 Based on this background and the need to identify targets to inhibit in combination with AKT that could synergize, a set of kinases were screened to identify those that could be targeted in combination with AKT3 to synergistically inhibit melanoma tumor development. WEE1 kinase was identified as a potential target that could accomplish this objective.…”

Section: Introductionmentioning

confidence: 99%

Identification of WEE1 as a target to make AKT inhibition more effective in melanoma

Kuzu

Gowda

Sharma

et al. 2017

Cancer Biology & Therapy

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AKT3 is one of the major therapeutic targets in melanoma but clinically targeting AKT3 alone seems to be an ineffective therapeutic approach. To identify unique strategies to enhance the efficacy of targeting AKT3, a screen was undertaken where AKT3 was co-targeted with a panel of kinases important in melanoma development. The screen identified WEE1 as the most potent target that when inhibited along with AKT3 would enhance the efficacy of targeting AKT3 in melanoma. RNAi mediated inhibition of AKT3 and WEE1 synergistically inhibited the viability of melanoma cells leading to a 65-75% decrease in tumor development. This approach was effective by mechanistically modulating pathways associated with the transcription factors p53 and FOXM1. Simultaneously regulating the activity of these two transcriptionally driven pathways, cooperatively deregulated cell cycle control and DNA damage repair to synergistically kill melanoma cells. This study uniquely identifies a potential approach to improve the efficacy of targeting AKT3 in melanoma.

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Phase II trial of trametinib in combination with the AKT inhibitor GSK 2141795 in BRAF wild-type melanoma.

Cited by 12 publications

References 0 publications

Maximising the potential of AKT inhibitors as anti-cancer treatments

Maximising the potential of AKT inhibitors as anti-cancer treatments

AKT in cancer: new molecular insights and advances in drug development

Identification of WEE1 as a target to make AKT inhibition more effective in melanoma

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