scholarly journals Acquired resistance to BRAFi reverses senescence-like phenotype in mutant BRAF melanoma

Oncotarget ◽  
2018 ◽  
Vol 9 (61) ◽  
pp. 31888-31903 ◽  
Author(s):  
Mohammad Krayem ◽  
Ahmad Najem ◽  
Fabrice Journe ◽  
Renato Morandini ◽  
François Sales ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Braf Melanoma ◽  
Mutant Braf

BH3-mimetic gossypol-induced autophagic cell death in mutant BRAF melanoma cells with high expression of p21Cip1

Life Sciences ◽  
2014 ◽  
Vol 102 (1) ◽  
pp. 41-48 ◽  
Author(s):  
Gun-Hee Jang ◽  
Michael Lee
Keyword(s):  
Cell Death ◽  
Melanoma Cells ◽  
Autophagic Cell Death ◽  
High Expression ◽  
Braf Melanoma ◽  
Mutant Braf ◽  
Bh3 Mimetic

scholarly journals Fibroblast-derived Neuregulin 1 Promotes Compensatory ErbB3 Receptor Signaling in Mutant BRAF Melanoma

2015 ◽  
Vol 290 (40) ◽  
pp. 24267-24277 ◽  
Author(s):  
Claudia Capparelli ◽  
Sheera Rosenbaum ◽  
Adam C. Berger ◽  
Andrew E. Aplin
Keyword(s):  
Receptor Signaling ◽  
Neuregulin 1 ◽  
Braf Melanoma ◽  
Mutant Braf

scholarly journals PERK mediates resistance to BRAF inhibition in melanoma with impaired PTEN

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Yifei Qin ◽  
Qiang Zuo ◽  
Lei Huang ◽  
Liping Huang ◽  
Glenn Merlino ◽  
...  
Keyword(s):  
Critical Role ◽  
Acquired Resistance ◽  
Braf Inhibitor ◽  
Treatment Needs ◽  
Braf Inhibition ◽  
Melanoma Treatment ◽  
Pten Inhibition ◽  
Mutant Braf

AbstractTargeting mutant BRAF in patients with melanomas harboring this oncogene has been highly successful as a first-line treatment, but other mutations may affect its efficacy and alter the route of acquired resistance resulting in recurrence and poor prognosis. As an evolving strategy, melanoma treatment needs to be expanded to include targets based on newly discovered emerging molecules and pathways. We here show that PERK plays a critical role in BRAF inhibitor-acquired resistance in melanoma with impaired PTEN. Inhibition of PERK by either shRNA or a pharmacological inhibitor blocked the growth of BRAF inhibitor-resistant melanoma with impaired PTEN in vitro and in vivo, suggesting an effective approach against melanomas with mutant BRAF and PTEN deficiency. Our current findings, along with our previous discovery that the AXL/AKT axis mediates resistance to BRAF inhibition in melanoma with wild-type PTEN, provide new insights toward a strategy for combating BRAF inhibition-acquired resistance in BRAF mutant melanoma with different PTEN statuses.

scholarly journals Oncogene Overdose: Too Much of a Bad Thing for Oncogene-Addicted Cancer Cells

2015 ◽  
Vol 7s2 ◽  
pp. BIC.S29326
Author(s):  
Amit Dipak Amin ◽  
Soumya S. Rajan ◽  
Matthew J. Groysman ◽  
Praechompoo Pongtornpipat ◽  
Jonathan H. schatz
Keyword(s):  
Cell Lymphoma ◽  
Acquired Resistance ◽  
Large Cell ◽  
Tumor Control ◽  
Resistance Mutations ◽  
Oncogenic Signaling ◽  
Anaplastic Lymphoma ◽  
Clinical Scenarios ◽  
Targeted Inhibitors ◽  
Mutant Braf

Acquired resistance to targeted inhibitors remains a major, and inevitable, obstacle in the treatment of oncogene-addicted cancers. Newer-generation inhibitors may help overcome resistance mutations, and inhibitor combinations can target parallel pathways, but durable benefit to patients remains elusive in most clinical scenarios. Now, recent studies suggest a third approach may be available in some cases—exploitation of oncogene overexpression that may arise to promote resistance. Here, we discuss the importance of maintaining oncogenic signaling at “just-right” levels in cells, with too much signaling, or oncogene overdose, being potentially as detrimental as too little. This is highlighted in particular by recent studies of mutant-BRAF in melanoma and the fusion kinase nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) in anaplastic large cell lymphoma. Oncogene overdose may be exploitable to prolong tumor control through intermittent dosing in some cases, and studies of acute lymphoid leukemias suggest that it may be specifically pharmacologically inducible.

scholarly journals Mutant-selective degradation by BRAF-targeting PROTACs

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shanique Alabi ◽  
Saul Jaime-Figueroa ◽  
Zhan Yao ◽  
Yijun Gao ◽  
John Hines ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Xenograft Model ◽  
Braf Inhibitor ◽  
Therapeutic Window ◽  
Missense Mutations ◽  
Cancer Cell Growth ◽  
Selective Degradation ◽  
Approved Drugs ◽  
Mutant Braf

AbstractOver 300 BRAF missense mutations have been identified in patients, yet currently approved drugs target V600 mutants alone. Moreover, acquired resistance inevitably emerges, primarily due to RAF lesions that prevent inhibition of BRAF V600 with current treatments. Therefore, there is a need for new therapies that target other mechanisms of activated BRAF. In this study, we use the Proteolysis Targeting Chimera (PROTAC) technology, which promotes ubiquitination and degradation of neo-substrates, to address the limitations of BRAF inhibitor-based therapies. Using vemurafenib-based PROTACs, we achieve low  nanomolar degradation of all classes of BRAF mutants, but spare degradation of WT RAF family members. Our lead PROTAC outperforms vemurafenib in inhibiting cancer cell growth and shows in vivo efficacy in a Class 2 BRAF xenograft model. Mechanistic studies reveal that BRAFWT is spared due to weak ternary complex formation in cells owing to its quiescent inactivated conformation, and activation of BRAFWT sensitizes it to degradation. This study highlights the degree of selectivity achievable with degradation-based approaches by targeting mutant BRAF-driven cancers while sparing BRAFWT, providing an anti-tumor drug modality that expands the therapeutic window.

Abstract 4807: FOXD3 regulates Rnd3 and invasion in mutant BRAF melanoma cells

2010 ◽  
Author(s):  
Pragati Dixit Katiyar ◽  
Ethan V. Abel ◽  
Andrew E. Aplin
Keyword(s):  
Melanoma Cells ◽  
Braf Melanoma ◽  
Mutant Braf

scholarly journals Mutant-selective Degradation by BRAF-targeting PROTACs

2020 ◽  
Author(s):  
Shanique Alabi ◽  
Saul Jaime-Figueroa ◽  
Zhan Yao ◽  
Yijun Gao ◽  
John Hines ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Xenograft Model ◽  
Braf Inhibitor ◽  
Therapeutic Window ◽  
Missense Mutations ◽  
Cancer Cell Growth ◽  
Selective Degradation ◽  
Approved Drugs ◽  
Mutant Braf

AbstractOver 300 BRAF missense mutations have been identified in patients, yet currently approved drugs target V600 mutants alone. Moreover, acquired resistance inevitably emerges, primarily due to RAF lesions that prevent inhibition of BRAF V600 with current treatments. Therefore, there is a need for new therapies that target other mechanisms of activated BRAF. In this study, we use the Proteolysis Targeting Chimera (PROTAC) technology, which promotes ubiquitination and degradation of neo-substrates, to address the limitations of BRAF inhibitor-based therapies. Using vemurafenib-based PROTACs, we successfully achieve sub-nanomolar degradation of all classes of BRAF mutants, but spare degradation of WT RAF family members. Our lead PROTAC outperforms vemurafenib in inhibiting cancer cell growth and shows in vivo efficacy in a Class 2 BRAF xenograft model. Mechanistic studies reveal that BRAFWT is spared due to weak ternary complex formation in cells owing to its quiescent inactivated conformation, and activation of BRAFWT sensitizes it to degradation. This study highlights the degree of selectivity achievable using degradation-based therapies by targeting mutant BRAF-driven cancers while sparing BRAFWT and thus expanding the therapeutic window using a new anti-tumor drug modality.

scholarly journals SPRED1 deletion confers resistance to MAPK inhibition in melanoma

2020 ◽  
Vol 218 (3) ◽  
Author(s):  
Julien Ablain ◽  
Sixue Liu ◽  
Gatien Moriceau ◽  
Roger S. Lo ◽  
Leonard I. Zon
Keyword(s):  
Melanoma Cell ◽  
Acquired Resistance ◽  
Human Melanoma ◽  
Functional Evaluation ◽  
Mapk Activity ◽  
Braf Inhibition ◽  
Novel Therapeutic Strategies ◽  
Mutant Braf

Functional evaluation of genetic lesions can discover a role in cancer initiation and progression and help develop novel therapeutic strategies. We previously identified the negative MAPK regulator SPRED1 as a novel tumor suppressor in KIT-driven melanoma. Here, we show that SPRED1 is also frequently deleted in human melanoma driven by mutant BRAF. We found that SPRED1 inactivation in human melanoma cell lines and primary zebrafish melanoma conferred resistance to BRAFV600E inhibition in vitro and in vivo. Mechanistically, SPRED1 loss promoted melanoma cell proliferation under mutant BRAF inhibition by reactivating MAPK activity. Consistently, biallelic deletion of SPRED1 was observed in a patient whose melanoma acquired resistance to MAPK-targeted therapy. These studies combining work in human cells and in vivo modeling in zebrafish demonstrate a new mechanism of resistance to BRAFV600E inhibition in melanoma.

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