Cell cycle control as a promising target in melanoma

Lee, Belinda; Sandhu, Shahneen; McArthur, Grant A.

doi:10.1097/cco.0000000000000159

Cited by 63 publications

(56 citation statements)

References 39 publications

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“…The addition of a third drug might help to overcome resistance and several trials are ongoing testing the triple combination of MEK plus BRAF inhibitors with MET, (46,47). It has been demonstrated that in resistant melanoma cell lines harboring BRAF splicing forms or BRAF amplifications stopping BRAF inhibition, leads to melanoma regression (48,49).…”

Section: Strategies To Overcome Resistancementioning

confidence: 99%

Resistant mechanisms to BRAF inhibitors in melanoma

Manzano¹,

et al. 2016

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Patients with advanced melanoma have traditionally had very poor prognosis. However, since 2011 better understanding of the biology and epidemiology of this disease has revolutionized its treatment, with newer therapies becoming available. These newer therapies can be classified into immunotherapy and targeted therapy.The immunotherapy arsenal includes inhibitors of CTLA4, PD-1 and PDL-1, while targeted therapy focuses on BRAF and MEK. BRAF inhibitors (vemurafenib, dabrafenib) have shown benefit in terms of overall survival (OS) compared to chemotherapy, and their combination with MEK inhibitors has recently been shown to improve progression-free survival (PFS), compared with monotherapy with BRAF inhibitors. However, almost 20% of patients initially do not respond, due to intrinsic resistance to therapy and, of those who do, most eventually develop mechanisms of acquired resistance, including reactivation of the MAP kinase pathway, persistent activation of receptor tyrosine kinase (RTKS) receptor, activation of phosphatidyinositol-3OH kinase, overexpression of epidermal growth factor receptor (EGFR), and interactions with the tumor microenvironment. Herein we comment in detail on mechanisms of resistance to targeted therapy and discuss the strategies to overcome them.

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Section: Strategies To Overcome Resistancementioning

confidence: 99%

Resistant mechanisms to BRAF inhibitors in melanoma

Manzano¹,

et al. 2016

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“…2,3,25 The results of our synergy studies using matched vemurafenib-sensitive and vemurafenib-resistant A375 and K4 cell lines are particularly intriguing and support the therapeutic strategy of combining CDK inhibitors with targeted MAPK therapies. To explain the mechanism of this synergy would be highly speculative, however, further exploration of the physiologic mechanisms responsible for the synergy of these drug combinations is needed to elucidate and fine-tune their potential therapeutic benefits.…”

Section: Ink4amentioning

confidence: 93%

“…2 Alterations in this pathway that lead to amplified CDK4 pathway signaling and aberrant cell proliferation have been clinically correlated to increased melanoma risk. Patients harboring germline homozygous deletions and loss-offunction (LOF) mutations in CDKN2A (the gene encoding the p16 INK4A protein) and activating mutations in CDK4 are 50 times more likely to develop melanoma.…”

Section: Ink4amentioning

confidence: 99%

“…An overwhelming majority of melanomas harbor genomic alterations in the CDK4 pathway, and it has been demonstrated that such alterations may be drivers of melanomagenesis or tumor progression, which would suggest a dependency on the key oncogenes in this pathway. [1][2][3][4][5] The success of vemurafenib and dabrafenib, selective BRAF V600E inhibitors, in melanoma gave credence to the strategy of targeting oncogene addiction, and in this light, many inhibitors of the CDK4 pathway are being investigated for potential therapeutic benefit.…”

Section: Introductionmentioning

confidence: 99%

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A novel multi-CDK inhibitor P1446A-05 restricts melanoma growth and produces synergistic effects in combination with MAPK pathway inhibitors

Eliades

Miller

Miao

et al. 2016

Cancer Biology & Therapy

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Nearly 100% of melanomas have a defect in the p16 INK4A:cyclin D-CDK4/6:RB pathway, leading to abnormal cell cycle control and unregulated cellular proliferation. Here, we report that P1446A-05, a novel multi-CDK inhibitor has significant inhibitory activity against cutaneous and uveal melanoma. Mechanistic studies revealed that P1446A-05 inhibits phosphorylation targets of CDK members, and induces cell cycle arrest and apoptosis irrespective of melanoma genotype or phenotype. Additionally, we show preclinical evidence that P1446A-05 can synergize with other small molecule inhibitors previously studied in melanoma. Collectively, these data demonstrate that targeting cell cycle and transcriptional CDKs with a small molecule multi-CDK inhibitor is a viable approach for developing novel anti-melanoma therapeutics.

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“…113 A number of alterations concerning the p16 INK4A :cyclin D-CDK4/6:RB pathway have been reported in melanoma. 7,114 Several different orally bioavailable, specific small molecule inhibitors of CDK 4 and 6 are currently available. By targeting CDK4/6, they inhibit phosphorylation of retinoblastoma protein and thus prevent CDK-mediated G1-S phase transition.…”

Section: Perspectivementioning

confidence: 99%

Developments in targeted therapy in melanoma

Amann

Ramelyte

Thurneysen

et al. 2017

European Journal of Surgical Oncology (EJSO)

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Melanomas are disease entities driven in part by the mitogen activated protein kinase (MAPK) pathway. The TCGA network recently defined four genetic subtypes based on the most prevalent significantly mutated genes, including mutant BRAF, mutant RAS (N/H/K), mutant NF1, and Triple wild-type melanoma (harboring none of the aforementioned mutations, but instead includes KIT, GNA and GNAQ mutations). The successful development of kinase inhibitors marked a milestone in the treatment of metastatic melanoma. Combination treatment with a BRAF-and MEK-inhibitor is the current standard of care for inoperable stage IIIC/IV BRAF-mutated melanoma. Recent data demonstrate excellent longterm outcome, especially in patients with normal baseline LDH levels, and confirm that there is a subset of BRAF inhibitor-naive patients who experience durable responses without progression on combination treatment. In the future, adding a third compound based on individual genetic alterations might further improve the outcome of targeted therapy. AbstractMelanomas are disease entities driven in part by the mitogen activated protein kinase (MAPK) pathway. The TCGA network recently defined four genetic subtypes based on the most prevalent significantly mutated genes, including mutant BRAF, mutant RAS (N/H/K), mutant NF1, and Triple wild-type melanoma (harboring none of the aforementioned mutations, but instead includes KIT, GNA and GNAQ mutations).The successful development of kinase inhibitors marked a milestone in the treatment of metastatic melanoma. Combination treatment with a BRAF-and MEK-inhibitor is the current standard of care for inoperable stage IIIC/IV BRAF-mutated melanoma. Recent data demonstrate excellent long-term outcome, especially in patients with normal baseline LDH levels, and confirm that there is a subset of BRAF inhibitor-naive patients who experience durable responses without progression on combination treatment. In the future, adding a third compound based on individual genetic alterations might further improve the outcome of targeted therapy.

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Cell cycle control as a promising target in melanoma

Abstract: http://links.lww.com/COON/A12.

Cited by 63 publications

References 39 publications

Resistant mechanisms to BRAF inhibitors in melanoma

Resistant mechanisms to BRAF inhibitors in melanoma

A novel multi-CDK inhibitor P1446A-05 restricts melanoma growth and produces synergistic effects in combination with MAPK pathway inhibitors

Developments in targeted therapy in melanoma

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