Exth-42. preclinical investigation of a novel brain penetrant mek inhibitor to target brain metastasis

Erika Yamazawa,Naema Nayyar,Nazanin Ijad,Consuelo Torrini,Magali de Sauvage, Christian Migliarese, Elizabeth Summers, Braxton Marion,Catherine Lee, Rowena Suriben, Michelle Salazar Pérez, B. J. Powell,Nichol L.G. Miller, Brooke Grandinetti,Hiroaki Wakimoto,Priscilla K. Brastianos

Neuro-oncology(2023)

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Abstract
Abstract Melanoma is one of the most common cancers with a high rate of brain metastases, with up to 75% of cases showing brain metastases upon autopsy. BRAF mutations are common in melanoma and found in up to 50-55% of melanoma brain metastases. Despite the clinical success of BRAF/MEK inhibitors for the treatment of advanced melanoma, dabrafenib and vemurafenib have limited intracranial overall response rates of 42-50% and median progression-free survival of 3.6-5.5 months. This limited efficacy is in part attributed to minimal blood-brain barrier penetration of the current available inhibitors. The goal of this study was to characterize a novel MEK inhibitor KIN-7136 as a potential therapeutic agent for brain metastasis driven by aberrant BRAF-MEK signaling, such as BRAF-mutant melanoma, using in vitro assays and an in vivo model of metastasis. KIN-7136 showed improved rodent brain exposure compared to conventional agents; the brain-to-plasma concentration ratio (Kp) of KIN-7136 was >1.0, much higher than comparators binimetinib and mirdametinib. In vitro cell viability assays showed potent cytotoxic effects of KIN-7136, with IC50s ranging from 15.4 to 204.9 nM in models of MAPK dysregulation including A375 (melanoma, BRAFV600E), NCI-H2405 (lung adenocarcinoma, BRAFΔNVTAP), HMVII (melanoma, BRAFG469V), and LN001 (patient derived lung adenocarcinoma, KRASG12V). Western blotting for phospho-ERK confirmed KIN-7136-mediated on-target downstream suppression in the A375 cell line. In vivo, daily oral treatment with KIN-7136 was well tolerated and produced a significant extension of overall survival compared to the vehicle control (p=0.0289, log-rank test) in the A375 intracranial tumor model in athymic mice. These preclinical data confirm activity of KIN-7136 in BRAF-mutant melanoma brain metastases models and support further research to advance its clinical progression.
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Key words
target brain metastasis,brain metastasis,inhibitor
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