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

Thomas S.C. Ng, Huiyu Hu, Stefan Kronister, Chanseo Lee, Ran Li, Luca Gerosa, Sylwia A. Stopka, Danielle M. Burgenske, Ishaan Khurana, Michael S. Regan, Sreeram Vallabhaneni, Niharika Putta, Ella Scott, Dylan Matvey, Anita Giobbie-Hurder, Rainer H. Kohler, Jann N. Sarkaria, Sareh Parangi, Peter K. Sorger, Nathalie Y.R. AgarHeather A. Jacene, Ryan J. Sullivan, Elizabeth Buchbinder, Hannes Mikula, Ralph Weissleder, Miles A. Miller

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numbereabl6339
JournalScience Advances
Issue number17
StatePublished - Apr 2022

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Overcoming differential tumor penetration of BRAF inhibitors using computationally guided combination therapy'. Together they form a unique fingerprint.

Cite this