Article

Inhibition of Mutated, Activated BRAF in Metastatic Melanoma

Abramson Cancer Center of the University of Pennsylvania, Philadelphia, USA.
New England Journal of Medicine (Impact Factor: 55.87). 08/2010; 363(9):809-19. DOI: 10.1056/NEJMoa1002011
Source: PubMed

ABSTRACT

The identification of somatic mutations in the gene encoding the serine-threonine protein kinase B-RAF (BRAF) in the majority of melanomas offers an opportunity to test oncogene-targeted therapy for this disease.
We conducted a multicenter, phase 1, dose-escalation trial of PLX4032 (also known as RG7204), an orally available inhibitor of mutated BRAF, followed by an extension phase involving the maximum dose that could be administered without adverse effects (the recommended phase 2 dose). Patients received PLX4032 twice daily until they had disease progression. Pharmacokinetic analysis and tumor-response assessments were conducted in all patients. In selected patients, tumor biopsy was performed before and during treatment to validate BRAF inhibition.
A total of 55 patients (49 of whom had melanoma) were enrolled in the dose-escalation phase, and 32 additional patients with metastatic melanoma who had BRAF with the V600E mutation were enrolled in the extension phase. The recommended phase 2 dose was 960 mg twice daily, with increases in the dose limited by grade 2 or 3 rash, fatigue, and arthralgia. In the dose-escalation cohort, among the 16 patients with melanoma whose tumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily, 10 had a partial response and 1 had a complete response. Among the 32 patients in the extension cohort, 24 had a partial response and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months.
Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients. (Funded by Plexxikon and Roche Pharmaceuticals.)

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    • "However, this appears to not be the case, as several examples show an exquisite sensitivity in both the primary lesion and distant metastatic lesions to the continued activity of the initiating oncogenic mutation. Although the published record of this dependency in experimental models is still short (Moody et al. 2002; Gunther et al. 2003; Shachaf et al. 2004; Dankort et al. 2009), it faithfully recapitulates clinical situations where effective targeted therapies are used to treat patients with metastatic cancer (Stahel et al. 2003; Hotta et al. 2004; Schneeweiss et al. 2004; Flaherty et al. 2010). These observations argue that metastasis-promoting mutations are not, in many instances, capable of protecting the metastatic lesions from therapeutics that inhibit the primary oncogenic driver. "

    Preview · Article · Feb 2016
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    • "Two selective BRAF kinase inhibitors have been approved for treatment of BRAF mutant metastatic melanomas. These drugs yield significant tumor regression, but most patients develop resistance that induces relapse (Flaherty et al. 2010; Holderfield et al. 2014). This reinforces the need to elucidate mechanisms of melanoma metastasis. "
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    ABSTRACT: Melanoma can switch between proliferative and invasive states, which have identifying gene expression signatures that correlate with good and poor prognosis, respectively. However, the mechanisms controlling these signatures are poorly understood. In this study, we identify BMI1 as a key determinant of melanoma metastasis by which its overexpression enhanced and its deletion impaired dissemination. Remarkably, in this tumor type, BMI1 had no effect on proliferation or primary tumor growth but enhanced every step of the metastatic cascade. Consistent with the broad spectrum of effects, BMI1 activated widespread gene expression changes, which are characteristic of melanoma progression and also chemoresistance. Accordingly, we showed that up-regulation or down-regulation of BMI1 induced resistance or sensitivity to BRAF inhibitor treatment and that induction of noncanonical Wnt by BMI1 is required for this resistance. Finally, we showed that our BMI1-induced gene signature encompasses all of the hallmarks of the previously described melanoma invasive signature. Moreover, our signature is predictive of poor prognosis in human melanoma and is able to identify primary tumors that are likely to become metastatic. These data yield key insights into melanoma biology and establish BMI1 as a compelling drug target whose inhibition would suppress both metastasis and chemoresistance of melanoma.
    Preview · Article · Dec 2015 · Genes & development
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    • "Frequent BRAF mutations led to the development of mutated BRAF inhibitors for the treatment of melanomas [2] [3]. However, the emergence of acquired resistance to BRAF inhibitors limited their effectiveness in the treatment of melanoma [4]. Our findings showed that gossypol retained its efficacy even after long-term treatment. "
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    ABSTRACT: Previously, we demonstrated the association between autophagy and gossypol-induced growth inhibition of mutant BRAF melanoma cells. Here, we investigate the role of autophagy in ATG5 knockout cell lines generated by the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas-mediated genome editing. The MTT assay revealed that the inhibitory effect of gossypol was weaker on ATG5 knockout cells than that on the wild type (WT) cells. The conversion of non-autophagic LC3-I to autophagic LC3-II and RT-PCR confirmed the functional gene knockout. However, Cyto-ID autophagy assay revealed that gossypol induced ATG5- and LC3-independent autophagy in ATG5 knockout cells. Moreover, gossypol acts as an autophagy inducer in ATG5 knockout cells while blocking the later stages of the autophagy process in WT cells, which was determined by measuring autophagic flux after co-treatment of gossypol with chloroquine (late-stage autophagy inhibitor). On the other hand, inhibition of autophagy with 3-MA or Beclin-1 siRNA caused a partial increase in the sensitivity to gossypol in ATG5 knockout cells, but not in the WT cells. Together, our findings suggest that the resistance to gossypol in ATG5 knockout cells is associated with increased cytoprotective autophagy, independent of ATG5.
    Full-text · Article · Oct 2015 · Cancer letters
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