Dataset Information

Integrated Genomics Identifies miR-32/MCL-1 Pathway as a Critical Driver of Melanomagenesis: Implications for miR-Replacement and Combination Therapy.

ABSTRACT:

Aims

Cutaneous malignant melanoma is among the deadliest human cancers, broadly resistant to most clinical therapies. A majority of patients with BRAFV600E melanomas respond well to inhibitors such as vemurafenib, but all ultimately relapse. Moreover, there are no viable treatment options available for other non-BRAF melanoma subtypes in the clinic. A key to improving treatment options lies in a better understanding of mechanisms underlying melanoma progression, which are complex and heterogeneous.

Methods

In this study we integrated gene and microRNA (miRNA) expression data from genetically engineered mouse models of highly and poorly malignant melanocytic tumors, as well as available human melanoma databases, and discovered an important role for a pathway centered on a tumor suppressor miRNA, miR-32.

Results

Malignant tumors frequently exhibited poor expression of miR-32, whose targets include NRAS, PI3K and notably, MCL-1. Accordingly, MCL-1 was often highly expressed in melanomas, and when knocked down diminished oncogenic potential. Forced MCL-1 overexpression transformed immortalized primary mouse melanocytes, but only when also expressing activating mutations in BRAF, CRAF or PI3K. Importantly, both miR-32 replacement therapy and the MCL-1-specific antagonist sabutoclax demonstrated single-agent efficacy, and acted synergistically in combination with vemurafenib in preclinical melanoma models.

Conclusions

We here identify miR-32/MCL-1 pathway members as key early genetic events driving melanoma progression, and suggest that their inhibition may be an effective anti-melanoma strategy irrespective of NRAS, BRAF, and PTEN status.

SUBMITTER: Mishra PJ

PROVIDER: S-EPMC5113037 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Integrated Genomics Identifies miR-32/MCL-1 Pathway as a Critical Driver of Melanomagenesis: Implications for miR-Replacement and Combination Therapy.

Mishra Prasun J PJ Mishra Pravin J PJ Merlino Glenn G

PloS one 20161115 11

<h4>Aims</h4>Cutaneous malignant melanoma is among the deadliest human cancers, broadly resistant to most clinical therapies. A majority of patients with BRAFV600E melanomas respond well to inhibitors such as vemurafenib, but all ultimately relapse. Moreover, there are no viable treatment options available for other non-BRAF melanoma subtypes in the clinic. A key to improving treatment options lies in a better understanding of mechanisms underlying melanoma progression, which are complex and het ...[more]

PMID: 27846237

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Project description:High levels of BCL-2 family proteins are implicated in a failed/ineffective apoptotic programme, often resulting in diseases, including cancer. Owing to their potential as drug targets in cancer therapy, several inhibitors of BCL-2 family proteins have been developed. These primarily target specific members of the BCL-2 family, particularly BCL-2 and BCL-XL but are ineffective against MCL-1. Major efforts have been invested in developing inhibitors of MCL-1, which is commonly amplified in human tumours and associated with tumour relapse and chemoresistance. In this report, the specificity of several BCL-2 family inhibitors (ABT-263, UCB-1350883, apogossypol and BH3I-1) was investigated and compared with putative MCL-1 inhibitors designed to exhibit improved or selective binding affinities for MCL-1 (TW-37, BI97C1, BI97C10, BI112D1, compounds 6 and 7, and MCL-1 inhibitor molecule (MIM-1)). ABT-263, BI97C1, BI112D1, MIM-1 and TW-37 exhibited specificity in inducing apoptosis in a Bax/Bak- and caspase-9-dependent manner, whereas the other agents showed no killing activity, or little or no specificity. Of these inhibitors, only ABT-263 and UCB-1350883 induced apoptosis in a BCL-2- or BCL-XL-dependent system. In cells that depend on MCL-1 for survival, ABT-263 and TW-37 induced extensive apoptosis, suggesting that at high concentrations these inhibitors have the propensity to inhibit MCL-1 in a cellular context. TW-37 induced apoptosis, assessed by chromatin condensation, caspase processing and phosphatidylserine externalisation, in a BAK-dependent manner and in cells that require MCL-1 for survival. TW-37-mediated apoptosis was also partly dependent on NOXA, suggesting that derivatives of TW-37, if engineered to exhibit better selectivity and efficacy at low nanomolar concentrations, may provide useful lead compounds for further synthetic programmes. Expanded medicinal chemistry iteration, as performed for the ABT series, may likewise improve the potency and specificity of the evaluated MCL-1 inhibitors.

Dataset Information

Integrated Genomics Identifies miR-32/MCL-1 Pathway as a Critical Driver of Melanomagenesis: Implications for miR-Replacement and Combination Therapy.

Aims

Methods

Results

Conclusions

Publications

Integrated Genomics Identifies miR-32/MCL-1 Pathway as a Critical Driver of Melanomagenesis: Implications for miR-Replacement and Combination Therapy.

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