Preclinical discovery and clinical development of encorafenib for the treatment of melanoma

Ökten, İlker; Ismail, Sadeka; Withycombe, Bethany; Eroglu, Zeynep

doi:10.1080/17460441.2020.1795124

Cited by 9 publications

(4 citation statements)

References 39 publications

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“…Deregulation of RAS-RAF-MEK-ERK signaling pathway promotes cell proliferation and survival, and RAS and RAF mutations are common in various cancers, which promoted the development of ATP-competitive RAF inhibitors [29]. So far, three selective BRAF inhibitors, Vemurafenib, Encorafenib, and Dabrafenib, have been approved by FDA for the treatment of melanoma harboring BRAF-V600E/K and obtained good clinical e cacy [14][15][16]. However, these inhibitors adopted a binding mode of αC-out conformation, in which the binding of the rst protomer would reduce the a nity of the second protomer by stabilizing the αC helix of the second protomer toward the IN position.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, to circumvent the di culty in pharmaceutical inhibition against RAS, the development of inhibitors targeting RAF is currently one of the main strategies for the treatment of RAS and BRAF mutant tumors. Until now, selective BRAF inhibitors Vemurafenib (PLX4032), Dabrafenib, and Encorafenib (LGX818) have been approved by FDA for the treatment of melanoma harboring BRAF-V600E/K mutations and obtained good clinical e cacy [14][15][16]. However, these drugs have week CRAF activities and show limited inhibition against RAS mutant tumors, in which the mutant RAS induces the dimerization of BRAF and CRAF, and selective inhibiting BRAF alone can activate CRAF-CRAF homodimers and BRAF-CRAF heterodimers, leading to the activation of RAF signaling [17].…”

Section: Introductionmentioning

confidence: 99%

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Discovery of a highly potent pan-RAF inhibitor IHMT-RAF-128 for cancer treatment

Wang

Liu

et al. 2023

European Journal of Pharmacology

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovery of a highly potent pan-RAF inhibitor IHMT-RAF-128 for cancer treatment

Wang

Liu

et al. 2023

European Journal of Pharmacology

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“…The Encorafenib-Cetuximab (EGFR targeting antibody) combination was approved in April 2020 for the previously treated BRAFV600E metastatic CRC patients, after it was shown to signi cantly improve their overall and progression-free survival during the trial. The doublet therapy was selected being to be equally effective to the triplet protocol, but with slightly less (MEKi-related) adverse effects [27,28].…”

Section: Introductionmentioning

confidence: 99%

Antitumorigenic effect of combination treatment with BRAF inhibitor and cisplatin in colorectal cancer in vitro and in vivo

Koumaki,

Skarmalioraki,

Kosmidou

et al. 2024

Preprint

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Purpose In colorectal cancer (CRC), BRAF inhibitor (BRAFi) monotherapy appears ineffective, while cisplatin treatment is associated with adverse effects, drug resistance and reduced efficacy. Herein, we seek to explore a combinatorial approach to increase the likelihood of effectively killing colorectal cancer cells. Methods We examined the combined effect of BRAFi (PLX4720, Vemurafenib, Dabrafenib, Encorafenib) and cisplatin treatment in BRAFV600E-mutated (RKO, HT29, Colo-205) and BRAFwt (Caco-2) cell lines, as well as in mouse xenografts of RKO cells. Results Following cisplatin-only treatment, all cell lines showed accumulation within subG1 (apoptotic cells) and G2/M phases, as well as phosphorylation of ERK1/2 and H2AX. Following BRAFi-only treatment, BRAFV600E-mutated cells showed accumulation within G0/G1 phase, reduced distribution in the S and G2/M phases, inhibition of ERK1/2 phosphorylation and increased phosphorylation of H2AX. BRAFi had no effect on BRAFwt Caco-2 cell line. Combined BRAFi and cisplatin treatment synergistically decreased RKO cells viability, reduced phosphorylation of ERK1/2 and increased phosphorylation of H2AX. Importantly, in mouse xenografts of RKO cells, combined PLX4720 and cisplatin treatment showed superior therapeutic potential than each monotherapy (P < 0.001). Conclusion In in vitro and in vivo preclinical models, BRAFi and cisplatin combined treatment has shown an improved antitumor effect, rendering it a potential anticancer treatment strategy for BRAF-mutant colon cancer patients.

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“…Biodistribution barriers for biologics, nanotherapies, and infused cytotoxics are widely appreciated (9,10), but barriers affecting orally administered small-molecule drugs have received less attention despite mass spectrometry studies highlighting variable KI delivery (11)(12)(13). Active drug transport can restrict drug accumulation in tumors, particularly with respect to the blood-brain barrier (BBB) for intracranial lesions (14); vemurafenib, dabrafenib, and encorafenib are all substrates of multidrug efflux transporters ABCB1 (MDR1/P-glycoprotein) and ABCG2 (BCRP) (15)(16)(17)(18)(19). Drug delivery barriers cannot simply be overcome by increasing dose for all patients: Dose-limiting toxicities of oral KI can be substantial.…”

Section: Introductionmentioning

confidence: 99%

Overcoming differential tumor penetration of BRAF inhibitors using computationally guided combination therapy

Kronister

et al. 2022

Sci. Adv.

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BRAF-targeted kinase inhibitors (KIs) are used to treat malignancies including BRAF-mutant non–small cell lung cancer, colorectal cancer, anaplastic thyroid cancer, and, most prominently, melanoma. However, KI selection criteria in patients remain unclear, as are pharmacokinetic/pharmacodynamic (PK/PD) mechanisms that may limit context-dependent efficacy and differentiate related drugs. To address this issue, we imaged mouse models of BRAF-mutant cancers, fluorescent KI tracers, and unlabeled drug to calibrate in silico spatial PK/PD models. Results indicated that drug lipophilicity, plasma clearance, faster target dissociation, and, in particular, high albumin binding could limit dabrafenib action in visceral metastases compared to other KIs. This correlated with retrospective clinical observations. Computational modeling identified a timed strategy for combining dabrafenib and encorafenib to better sustain BRAF inhibition, which showed enhanced efficacy in mice. This study thus offers principles of spatial drug action that may help guide drug development, KI selection, and combination.

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Preclinical discovery and clinical development of encorafenib for the treatment of melanoma

Cited by 9 publications

References 39 publications

Discovery of a highly potent pan-RAF inhibitor IHMT-RAF-128 for cancer treatment

Discovery of a highly potent pan-RAF inhibitor IHMT-RAF-128 for cancer treatment

Antitumorigenic effect of combination treatment with BRAF inhibitor and cisplatin in colorectal cancer in vitro and in vivo

Overcoming differential tumor penetration of BRAF inhibitors using computationally guided combination therapy

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