ArticleProceedings of the National Academy of Sciences of the United States of America2013
BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 140 papers, 1 of them a synthesis that pooled it.
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Who cites it
140 citing papers in PubMed, 1 synthesis or guideline pooled it, 224 citations in OpenAlex.
- Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms.European journal of cancer (Oxford, England : 1990) · 2015Pooled it
- Reversing drug resistance of soft tumor-repopulating cells by tumor cell-derived chemotherapeutic microparticles.Cell research · 2016Trial
- Trial
- Imaging transcriptomics in basal cell carcinoma: Coupling in vivo tumor morphology with gene expression.JID innovations : skin science from molecules to population health · 2026Article
- MITF Is an Essential and Functionally Multifaceted Transcription Factor in Cutaneous Melanoma.Cancers · 2026Review
- Personalized targeting of BCL2 family proteins overcomes acquired resistance to BRAF-MEK inhibitors in preclinical melanoma.Nature communications · 2026Article
- Anti-apoptotic BCL-2 family proteins: from regulatory networks to therapeutic targeting.Oncogenesis · 2026Review
- Recombinant RGD-Apoptins Decrease Human Melanoma Cell Viability.International journal of molecular sciences · 2025Article
- Targeting the BCL2 Family: Advances and Challenges in BH3 Mimetic-Based Therapies.International journal of molecular sciences · 2025Review
- Mitochondrial bioenergetics and networks in melanoma: an update.Apoptosis : an international journal on programmed cell death · 2025Review
- The potential role of BCL2A1⁺ tissue-resident macrophages in the prognosis of Wilms tumor.European journal of medical research · 2025Article
- TIMM8B promotes oxidative phosphorylation and glycolysis by inhibiting the mtROS/ASK1/JNK signaling pathway in ovarian cancer.Biology direct · 2025Article
- COP1 Deficiency in BRAFCells · 2025Article
- Mitochondrial signatures shape phenotype switching and apoptosis in response to PLK1 inhibitors.Life science alliance · 2025Article
- Contribution of A1 to macrophage survival in cooperation with MCL-1 and BCL-XCell death & disease · 2024Article
- MITF regulates IDH1, NNT, and a transcriptional program protecting melanoma from reactive oxygen species.Scientific reports · 2024Article
- Genomic analysis reveals the association of KIT and MITF variants with the white spotting in swamp buffaloes.BMC genomics · 2024Article
- Review
- BRAF - a tumour-agnostic drug target with lineage-specific dependencies.Nature reviews. Clinical oncology · 2024Review
- An atlas of cell-type-specific interactome networks across 44 human tumor types.Genome medicine · 2024Article
80 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
18 authors at 11 institutions in 3 countries.
Funding
Abstract
Although targeting oncogenic mutations in the BRAF serine/threonine kinase with small molecule inhibitors can lead to significant clinical responses in melanoma, it fails to eradicate tumors in nearly all patients. Successful therapy will be aided by identification of intrinsic mechanisms that protect tumor cells from death. Here, we used a bioinformatics approach to identify drug-able, "driver" oncogenes restricted to tumor versus normal tissues. Applying this method to 88 short-term melanoma cell cultures, we show that the antiapoptotic BCL2 family member BCL2A1 is recurrently amplified in ∼30% of melanomas and is necessary for melanoma growth. BCL2A1 overexpression also promotes melanomagenesis of BRAF-immortalized melanocytes. We find that high-level expression of BCL2A1 is restricted to melanoma due to direct transcriptional control by the melanoma oncogene MITF. Although BRAF inhibitors lead to cell cycle arrest and modest apoptosis, we find that apoptosis is significantly enhanced by suppression of BCL2A1 in melanomas with BCL2A1 or MITF amplification. Moreover, we find that BCL2A1 expression is associated with poorer clinical responses to BRAF pathway inhibitors in melanoma patients. Cotreatment of melanomas with BRAF inhibitors and obatoclax, an inhibitor of BCL2A1 and other BCL2 family members, overcomes intrinsic resistance to BRAF inhibitors in BCL2A1-amplified cells in vitro and in vivo. These studies identify MITF-BCL2A1 as a lineage-specific oncogenic pathway in melanoma and underscore its role for improved response to BRAF-directed therapy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.