BRAF paradox breakers PLX8394, PLX7904 are more effective against BRAFV600Ε CRC cells compared with the BRAF inhibitor PLX4720 and shown by detailed pathway analysis

Koumaki, Kassandra; Kontogianni, Georgia; Kosmidou, Vivian; Pahitsa, Fani; Kritsi, Eftichia; Zervou, Maria I.; Chatziioannou, Aristotelis; Souliotis, Vassilis L.; Papadodima, Olga; Pintzas, Alexander

doi:10.1016/j.bbadis.2020.166061

Cited by 21 publications

(16 citation statements)

References 56 publications

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“…It is a BRAF inhibitor that can be taken orally and does not lead to paradoxical activation of MAPK. − Compared to vemurafenib, PLX-7904 inhibits MAPK signaling for a longer period of time, resulting in greater blockade of proliferation and lower viability. In BRAF V600E melanoma cells, PLX-7904 was found to effectively suppress RAF signaling, whereas it had no paradoxical effects on wild-type cells. ,− RAF-265 is a dual inhibitor of BRAF and VEGFR2, preventing both osteoclast development and resorption. RAF-265 shows synergistic antitumor activity with ZSTK-474 in medullary thyroid cancer. ,− BGB-659 is able to inhibit class I and class II BRAF mutations because it can bind both monomeric BRAFs and both protomers of an RAF dimer.…”

Section: Current Insight Into Braf Inhibitorsmentioning

confidence: 98%

Challenges and Opportunities in the Crusade of BRAF Inhibitors: From 2002 to 2022

et al. 2023

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Serine/threonine-protein kinase B-Raf (BRAF; RAF = rapidly accelerated fibrosarcoma) plays an important role in the mitogen-activated protein kinase (MAPK) signaling cascade. Somatic mutations in the BRAF gene were first discovered in 2002 by Davies et al., which was a major breakthrough in cancer research. Subsequently, three different classes of BRAF mutants have been discovered. This class includes class I monomeric mutants (BRAF V600 ), class II BRAF homodimer mutants (non-V600), and class III BRAF heterodimers (non-V600). Cancers caused by these include melanoma, thyroid cancer, ovarian cancer, colorectal cancer, nonsmall cell lung cancer, and others. In this study, we have highlighted the major binding pockets in BRAF protein, their active and inactive conformations with inhibitors, and BRAF dimerization and its importance in paradoxical activation and BRAF mutation. We have discussed the first-, second-, and third-generation drugs approved by the Food and Drug Administration and drugs under clinical trials with all four different binding approaches with DFG-IN/OUT and αC-IN/ OUT for BRAF protein. We have investigated particular aspects and difficulties with all three generations of inhibitors. Finally, this study has also covered recent developments in synthetic BRAF inhibitors (from their discovery in 2002 to 2022), their unique properties, and importance in inhibiting BRAF mutants.

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Section: Current Insight Into Braf Inhibitorsmentioning

confidence: 98%

Challenges and Opportunities in the Crusade of BRAF Inhibitors: From 2002 to 2022

et al. 2023

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“…About 80% of drug resistant cases in BRAF V600E mutated tumors overall are thought to arise from the reactivation of MAPK pathway ( 60 ). Despite positive initial response to inhibitors such as Dabrafenib or Vemurafenib, it is well documented that cells can find alternative ways to activate the pro-survival MAPK pathway in many cancer subtypes ( 61 , 62 ), including gliomas ( 63 ). Secondary mutations in the MAPK pathway, BRAF copy number gains, BRAF alternative splicing as well as increased expression of receptor tyrosine kinases are some of the diverse mechanisms that can cause MAPK pathway reactivation ( 64 ).…”

Section: Resistance To Braf Inhibitionmentioning

confidence: 99%

Response and resistance to BRAFV600E inhibition in gliomas: Roadblocks ahead?

Capogiri

Micheli²,

Lassaletta³

et al. 2023

Front. Oncol.

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BRAFV600E represents the most common BRAF mutation in all human cancers. Among central nervous system (CNS) tumors, BRAFV600E is mostly found in pediatric low-grade gliomas (pLGG, ~20%) and, less frequently, in pediatric high-grade gliomas (pHGG, 5-15%) and adult glioblastomas (GBM, ~5%). The integration of BRAF inhibitors (BRAFi) in the treatment of patients with gliomas brought a paradigm shift to clinical care. However, not all patients benefit from treatment due to intrinsic or acquired resistance to BRAF inhibition. Defining predictors of response, as well as developing strategies to prevent resistance to BRAFi and overcome post-BRAFi tumor progression/rebound growth are some of the main challenges at present in the field. In this review, we outline current achievements and limitations of BRAF inhibition in gliomas, with a special focus on potential mechanisms of resistance. We discuss future directions of targeted therapy for BRAFV600E mutated gliomas, highlighting how insights into resistance to BRAFi could be leveraged to improve outcomes.

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“…These inhibitors disrupt the RAF dimer interface, preventing the induction of BRAF homodimers and BRAF-CRAF heterodimers. 60,61 A phase I/II trial evaluating the safety and efficacy of the paradox breaker PLX8394 in 45 patients with BRAF mutations or fusions reported a response rate of 22%. 62 Since the most common mechanisms of acquired resistance to BRAF inhibition converge on reactivation of ERK, substantial efforts are underway to develop direct ERK1/2 inhibitors.…”

Section: Ongoing and Future Braf V600e -Directed Clinical Trialsmentioning

confidence: 99%

Section: Ongoing and Future Brafv600e-directed Clinical Trialsmentioning

confidence: 99%

BRAF-Mutated Advanced Colorectal Cancer: A Rapidly Changing Therapeutic Landscape

Ciombor

Strickler

Bekaii‐Saab

et al. 2022

JCO

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BRAF-mutated advanced colorectal cancer is a relatively small but critical subset of this tumor type on the basis of prognostic and predictive implications. BRAF alterations in colorectal cancer are classified into three functional categories on the basis of signaling mechanisms, with the class I BRAF V600E mutation occurring most frequently in colorectal cancer. Functional categorization of BRAF mutations in colorectal cancer demonstrates distinct mitogen-activated protein kinase pathway signaling. On the basis of recent clinical trials, current standard-of-care therapies for patients with BRAF V600E -mutated metastatic colorectal cancer include first-line cytotoxic chemotherapy plus bevacizumab and subsequent therapy with the BRAF inhibitor encorafenib and antiepidermal growth factor receptor antibody cetuximab. Treatment regimens currently under exploration in BRAF V600E-mutant metastatic colorectal cancer include combinatorial options of various pathway-targeted therapies, cytotoxic chemotherapy, and/or immune checkpoint blockade, among others. Circumvention of adaptive and acquired resistance to BRAF-targeted therapies is a significant challenge to be overcome in BRAF-mutated advanced colorectal cancer.

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BRAF paradox breakers PLX8394, PLX7904 are more effective against BRAFV600Ε CRC cells compared with the BRAF inhibitor PLX4720 and shown by detailed pathway analysis

Cited by 21 publications

References 56 publications

Challenges and Opportunities in the Crusade of BRAF Inhibitors: From 2002 to 2022

Challenges and Opportunities in the Crusade of BRAF Inhibitors: From 2002 to 2022

Response and resistance to BRAFV600E inhibition in gliomas: Roadblocks ahead?

BRAF-Mutated Advanced Colorectal Cancer: A Rapidly Changing Therapeutic Landscape

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