PLX4032 and melanoma: resistance, expectations and uncertainty

Roukos, Dimitrios H

doi:10.1586/era.11.3

Cited by 12 publications

(10 citation statements)

References 21 publications

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“…However, there has been remarkable progress towards targeted melanoma therapy by targeting mutant BRAF , using KIT inhibitors or using antibody targeting cytototoxic T-lymphocyte-associated antigen 4 [40–42]. Nevertheless, the search for new drugs is mandatory, since melanomas develop resistance to such targeted therapy (of which the best example is the development of resistance to PLX4032; reviewed in [43]). As melanocytes are VDR-expressing cells, they are also potential targets for vitamin D. However, caution is needed in overestimating the importance of 1α,25-dihydroxyvitamin D3-based therapy, owing to recent findings that VDR expression decreases with the progression of melanoma [44].…”

Section: Melanomamentioning

confidence: 99%

New vitamin D analogs as potential therapeutics in melanoma

Szyszka

Żmijewski

Slominski

2012

Expert Review of Anticancer Therapy

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Extensive evidence shows that the active form of vitamin D3 – 1α,25-dihydroxyvitamin D3 – plays an important role in cancer prevention, has tumorostatic activity and may potentially be used in therapy for melanoma. Vitamin D3 and its analogs (secosteroids) exert multiple effects on cancer cells, including inhibition of cell growth and induction of differentiation. Activity of secosteroids depends on multiple cellular factors, including expression of the vitamin D receptor. Despite its endogenous origin, the key drawback for the use of pharmacologically effective doses of 1α,25-dihydroxyvitamin D3 is its hypercalcemic effect leading to profound toxicity. The solution may lie in properties of vitamin D3 analogs with modified side chains, which demonstrate low calcemic activity but conserve the anti-tumor properties. Noncalcemic vitamin D compounds were found to be potent in multiple studies that mandate further clinical testing. Finally, recent studies revealed alternative metabolic pathways for secosteroids and new targets in the cells, which opens up new therapeutic possibilities.

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Section: Melanomamentioning

confidence: 99%

New vitamin D analogs as potential therapeutics in melanoma

Szyszka

Żmijewski

Slominski

2012

Expert Review of Anticancer Therapy

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“…1 The prognosis of melanoma is poor, with the lower than 20% of 5-year survival rates for patients who harbor metastatic melanoma. 2,3 Since about 50% patients with melanoma have been found to harbor the activating BRAF V600E mutation, 4 the current targeted therapy focuses on RAS-RAF-MEK-ERK signaling pathway. 5 Even though the initial response to BRAF inhibitors (vemurafenib and dabrafenib) and MEK inhibitors (trametinib and cobimetinib) is impressive, resistance usually develops in the patients within 6–8 months.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-26a inhibits the growth and invasiveness of malignant melanoma and directly targets on MITF gene

2017

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Metastatic melanoma is the most aggressive form of skin cancer and is refractory to therapy. MicroRNAs have been recently discovered as novel molecules that provide therapeutic benefits against melanoma. This work aims to examine the effects of miR-26a and let-7a on the growth and invasiveness of malignant melanoma in vitro and in vivo. In addition, we elucidate the mechanism of action by identifying the target gene of miR-26a. Both miR-26a and let-7a inhibited proliferation and invasiveness and halted the cell cycle at the G 1 /G 0 phase in SKMEL-28 and WM1552C malignant melanoma cell lines. Moreover, miR-26a potently induced apoptosis and downregulated the expressions of microphthalmia-associated transcription factor (MITF) and MAP4K3 in both cell lines. The luciferase reporter assay demonstrated that miR-26a suppresses MITF expression by binding the 3′-UTR, suggesting that MITF is a bona fide target of miR-26a. SiRNA knockdown of the MITF gene confirmed that miR-26a reduced cell viability and induced apoptosis by regulating MITF. Using a murine model, we also found miR-26a significantly retarded the growth of melanoma tumors in vivo. In conclusion, miR-26a and let-7a suppressed the growth and invasiveness of melanoma cells, suggesting that miR-26a and let-7a may represent novel therapies for malignant melanoma.

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“…The most common mutation is BRAF V600E mutation, which results in a 500-fold increase in kinase activity, and is the target of PLX4032 inhibition (Flaherty et al, 2010b). Indeed, the results of Phase I/II trials have been promising, with a demonstrated response rate of up to 80% (Roukos, 2011). Exposure to drugs such as PLX4720 or PLX4032 results in a variety of anti-melanoma effects through the inhibition of the MAPK pathway and more specifically by mitigating aberrant activation of extracellular signal-regulated kinase (ERK), a downstream target of BRAF.…”

Section: Cell Fate As a Determinant Of Therapeutic Response 261 Thementioning

confidence: 99%

“…As a result, the use of PLX4720 or PLX4032 in cells harbouring activating mutations of BRAF such as BRAF V600E demonstrate decreased levels of proliferation, impaired colony-forming capability and the induction of apoptosis (Tsai et al, 2008). Despite obvious excitement over the demonstrated response rate of PLX4032 thus far, talk of accelerated FDA approval and current Phase III clinical trials, questions still remain regarding the potential benefit of this drug on overall patient survival (Roukos, 2011). …”

Section: Cell Fate As a Determinant Of Therapeutic Response 261 Thementioning

confidence: 99%