Clinical responses to AZD6244 (ARRY-142886)-based combination therapy stratified by gene mutations in patients with metastatic melanoma.

Patel, Sunil; Lazar, Alexander J.; Mahoney, Sandy; Vaughn, Carol; Gonzalez, N. Saoudi; Papadopoulos, N; Liu, P.; Infante, J. R.; LoRusso, Patricia; Kim, K. B.

doi:10.1200/jco.2010.28.15_suppl.8501

Cited by 20 publications

(15 citation statements)

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“…In this trial, the AZD6244 group had 6 confirmed responses, of which 5 carried mutant braf (65). In another phase I trial of AZD6244-based combination therapy, a positive trend was identified between braf mutation and clinical benefit (66). No such trend was identified for nras mutations.…”

Section: Targeting Mek In Mutant Braf Tumorsmentioning

confidence: 99%

BRAFV600E: Implications for Carcinogenesis and Molecular Therapy

Dorris¹,

O’Leary

Sheils

2011

Molecular Cancer Therapeutics

397

309

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The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway is frequently mutated in human cancer. This pathway consists of a small GTP protein of the RAS family that is activated in response to extracellular signaling to recruit a member of the RAF kinase family to the cell membrane. Active RAF signals through MAP/ERK kinase to activate ERK and its downstream effectors to regulate a wide range of biological activities including cell differentiation, proliferation, senescence, and survival. Mutations in the v-raf murine sarcoma viral oncogenes homolog B1 (BRAF) isoform of the RAF kinase or KRAS isoform of the RAS protein are found as activating mutations in approximately 30% of all human cancers. The BRAF pathway has become a target of interest for molecular therapy, with promising results emerging from clinical trials. Here, the role of the most common BRAF mutation BRAF V600E in human carcinogenesis is investigated through a review of the literature, with specific focus on its role in melanoma, colorectal, and thyroid cancers and its potential as a therapeutic target.

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Section: Targeting Mek In Mutant Braf Tumorsmentioning

confidence: 99%

BRAFV600E: Implications for Carcinogenesis and Molecular Therapy

Dorris¹,

O’Leary

Sheils

2011

Molecular Cancer Therapeutics

397

309

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“…51 Clinically, several agents including selumetinib (AZD6244), PD-0325901, trametinib (GSK1120212), AS703026 and MEK162 have been evaluated in patients with melanoma with variable success. 5,7,9,[52][53][54][55][56] The great majority of clinical benefit (defined as clinical response or improved survival) has been seen in patients with BRAF mutations, though emerging clinical evidence now has been described that supports a role of MEK inhibitors in treating patients with NRAS mutations. To date, none of the MEK inhibitors have resulted in clinical efficacy that is comparable to the selective BRAF inhibitors, though trametinib and MEK162 have recently been shown to be the most active MEK inhibitors thus far in BRAF mutant melanoma.…”

Section: Mek Inhibitorsmentioning

confidence: 98%

MAP kinase signaling and inhibition in melanoma

2012

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The mitogen-activated protein kinase (MAPK) pathway is critical to oncogenic signaling in the majority of patients with malignant melanoma. Driver mutations in both NRAS and BRAF have important implications for prognosis and treatment. The development of inhibitors to mediators of the MAPK pathway, including those to CRAF, BRAF, and MEK, has led to major advances in the treatment of patients with melanoma. In particular, the selective BRAF inhibitor vemurafenib has been shown to improve overall survival in patients with tumors harboring BRAF mutations. However, the duration of benefit is limited in many patients and highlights the need for understanding the limitations of therapy in order to devise more effective strategies. MEK inhibitors have proven to particularly active in BRAF mutant melanomas also. Emerging knowledge about mechanisms of resistance as well as a more complete understanding of the biology of MAPK pathway signaling provides insight into rational combination regimens and sequences of molecularly targeted therapies.

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“…BRAF inhibition, or its downstream protein MEK inhibition, can suppress the pathway. The proof of concept was observed in the phase I clinical study, where almost 70% of melanoma patients with such BRAF mutations responded to BRAF or MEK inhibitors [66,67]. However, resistance can occur and one of the main causes is the crosstalk between RAS/RAF/MAPK and PI3K-Akt pathways.…”

Section: Rationale Of Blocking Pi3k-akt Pathwaymentioning

confidence: 88%

Targeting phosphatidylinositol 3 kinase (PI3K)-Akt beyond rapalogs

Ogita

LoRusso

2011

Targ Oncol

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The activation of the phosphatidylinositol 3 kinase (PI3K)-Akt pathway is a known causal mechanism of oncogenesis and resistance to cancer treatments. The process of PI3K-Akt pathway activation is complex and includes receptor tyrosine kinase(RTK) activation, PIK3CA mutations, loss of phosphatase and tensin homolog (PTEN), Akt mutations, tuberous sclerosis complex (TSC) mutations, and Ras homologue enriched in brain (RHEB) gene amplifications. The blockage of mammalian target of rapamycin (mTOR), the key downstream pathway protein, has been successful in selected cancer types, with mTOR-targeting agents available for clinical use. Other novel drugs blocking this pathway such as PI3K inhibitors, Akt inhibitors and PDK-1 inhibitors are currently only available for investigational use, but have shown promise as cancer therapies in both preclinical and early phase clinical studies. The newer generations of these inhibitors are more specific and have improved potency and safety. The combinations of targeted treatments against this pathway, blocking multiple different steps, are under preliminary investigation. Further research is needed to identify the biomarkers that predict treatment response and resistance in order to optimize personalized medicine.

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Clinical responses to AZD6244 (ARRY-142886)-based combination therapy stratified by gene mutations in patients with metastatic melanoma.

Cited by 20 publications

References 0 publications

BRAFV600E: Implications for Carcinogenesis and Molecular Therapy

BRAFV600E: Implications for Carcinogenesis and Molecular Therapy

MAP kinase signaling and inhibition in melanoma

Targeting phosphatidylinositol 3 kinase (PI3K)-Akt beyond rapalogs

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