A randomized phase 2 study of trametinib with or without GSK2141795 in patients with advanced uveal melanoma.

Shoushtari, Alexander N.; Kudchadkar, Ragini R.; Panageas, Katherine S.; Murthy, Rashmi Krishna; Jung, Maria; Shah, Roshani; O’Donnell, Bridget A.; Khawaja, Talal T; Shames, Yelena; Prempeh-Keteku, Nana A.; Ambrosini, Grazia; Chen, Alice; Chapman, Paul B.; Schwartz, Gary K.; Patel, Sapna

doi:10.1200/jco.2016.34.15_suppl.9511

Cited by 50 publications

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“… 98 Unfortunately, a randomized, phase II trial evaluating the efficacy of trametinib with or without the Akt inhibitor GSK2141795 (GSK795) in 40 patients with metastatic uveal melanoma failed to detect any survival benefit with the addition of Akt inhibition. 99 Median PFS was 15.6 weeks in the GSK795 arm and 15.7 weeks in the trametinib alone arm. Only one partial response was observed in each arm (ORR ~5%), so accrual was held.…”

Section: Treatment Of Metastatic Uveal Melanomamentioning

confidence: 95%

Treatment of uveal melanoma: where are we now?

et al. 2018

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Uveal melanoma, a rare subset of melanoma, is the most common primary intraocular malignancy in adults. Despite effective primary therapy, nearly 50% of patients will develop metastatic disease. Outcomes for those with metastatic disease remain dismal due to a lack of effective therapies. The unique biology and immunology of uveal melanoma necessitates the development of dedicated management and treatment approaches. Ongoing efforts seek to optimize the efficacy of targeted therapy and immunotherapy in both the adjuvant and metastatic setting. This review provides a comprehensive, updated overview of disease biology and risk stratification, the management of primary disease, options for adjuvant therapy, and the current status of treatment strategies for metastatic disease.

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Section: Treatment Of Metastatic Uveal Melanomamentioning

confidence: 95%

Treatment of uveal melanoma: where are we now?

et al. 2018

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“…The coinhibition of MAPK and AKT pathways induced activation of AMP‐activated protein kinase and resulted in apoptosis (Ambrosini, Musi, Ho, De Stanchina, & Schwartz, ). These preclinical data resulted in a phase II clinical trial of 80 patients with metastatic UM combining selumetinib + GSK795 (AKT inhibitor) vs selumetinib alone, although the addition of AKT inhibitor did not improve PFS and RR was the same in both arms at 3% (Shoushtari, Kudchadkar et al., ).…”

Section: Oncogenic Signalingmentioning

confidence: 99%

Oncogenic signaling in uveal melanoma

Park

Diefenbach

Joshua

et al. 2018

Pigment Cell Melanoma Res

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Uveal melanoma is the most common primary cancer of the eye, and despite rapidly emerging insights into the molecular profile of this disease, prognosis of patients with metastatic uveal melanoma remains poor with mortality rates unchanged in over 35 years. Early genetic events activate G protein-coupled receptor signaling in nearly all uveal tumors via mutually exclusive mutations in the GNAQ, GNA11, CYSLTR2, or PLCB4 genes. A multitude of signaling cascades downstream of G protein activation, including protein kinase C and mitogen-activated protein kinase activity, are actionable, and many ongoing clinical trials are targeting these pathways. Additional cytogenetic and genetic changes, however, including chromosome 3 monosomy, mutations in the BAP1 tumor suppressor gene, alterations in the splicing factors SRSF2/SF3B1, and mutations in the translation initiation factor EIF1AX, modulate signaling output in uveal tumors and modify the risk of metastases. Here, we review the complex interactions between genetic, molecular signaling, and prognostic profiles in uveal melanoma; the clinical implications of these interactions; and the latest potential targets for rational therapy.

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“…Clinical investigations combining uprosertib with the MEK inhibitor trametinib in several cancers types have been underway, however, similar studies in multiple myeloma, melanoma and cervical cancer have revealed no clinical benefits of this combination. [43][44][45][46] Although uprosertib treatment as a monotherapy has been well tolerated, 22,23 the adverse toxicity profile of phase II combination studies has been deemed unacceptable, thus, uprosertib is not currently under further development. 46 Since we have demonstrated that enhanced OXPHOS in the presence of lactic acid is related to uprosertib resistance, and previous reports highlight that resistance to MEK combination therapies also corresponds with enhanced OXPHOS, 41 this metabolic phenotype should be considered as a possible contributor to the lack of clinical efficacy observed during phase II trials with uprosertib.…”

Section: Discussionmentioning

confidence: 99%

Lactic acidosis induces resistance to the pan-Akt inhibitor uprosertib in colon cancer cells

Barnes

Benito

et al. 2020

Br J Cancer

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BACKGROUND: Akt signalling regulates glycolysis and drives the Warburg effect in cancer, thus decreased glucose utilisation is a pharmacodynamic marker of Akt inhibition. However, cancer cells can utilise alternative nutrients to glucose for energy such as lactate, which is often elevated in tumours together with increased acidity. We therefore hypothesised that lactic acidosis may confer resistance to Akt inhibition. METHODS: The effect of the pan-Akt inhibitor uprosertib (GSK2141795), on HCT116 and LS174T colon cancer cells was evaluated in the presence and absence of lactic acid in vitro. Expression of downstream Akt signalling proteins was determined using a phosphokinase array and immunoblotting. Metabolism was assessed using 1 H nuclear magnetic resonance spectroscopy, stable isotope labelling and gas chromatography-mass spectrometry. RESULTS: Lactic acid-induced resistance to uprosertib was characterised by increased cell survival and reduced apoptosis. Uprosertib treatment reduced Akt signalling and glucose uptake irrespective of lactic acid supplementation. However, incorporation of lactate carbon and enhanced respiration was maintained in the presence of uprosertib and lactic acid. Inhibiting lactate transport or oxidative phosphorylation was sufficient to potentiate apoptosis in the presence of uprosertib. CONCLUSIONS: Lactic acidosis confers resistance to uprosertib, which can be reversed by inhibiting lactate transport or oxidative metabolism.

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A randomized phase 2 study of trametinib with or without GSK2141795 in patients with advanced uveal melanoma.

Cited by 50 publications

References 0 publications

Treatment of uveal melanoma: where are we now?

Treatment of uveal melanoma: where are we now?

Oncogenic signaling in uveal melanoma

Lactic acidosis induces resistance to the pan-Akt inhibitor uprosertib in colon cancer cells

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