TY - JOUR
T1 - Overcoming differential tumor penetration of BRAF inhibitors using computationally guided combination therapy
AU - Ng, Thomas S.C.
AU - Hu, Huiyu
AU - Kronister, Stefan
AU - Lee, Chanseo
AU - Li, Ran
AU - Gerosa, Luca
AU - Stopka, Sylwia A.
AU - Burgenske, Danielle M.
AU - Khurana, Ishaan
AU - Regan, Michael S.
AU - Vallabhaneni, Sreeram
AU - Putta, Niharika
AU - Scott, Ella
AU - Matvey, Dylan
AU - Giobbie-Hurder, Anita
AU - Kohler, Rainer H.
AU - Sarkaria, Jann N.
AU - Parangi, Sareh
AU - Sorger, Peter K.
AU - Agar, Nathalie Y.R.
AU - Jacene, Heather A.
AU - Sullivan, Ryan J.
AU - Buchbinder, Elizabeth
AU - Mikula, Hannes
AU - Weissleder, Ralph
AU - Miller, Miles A.
N1 - Publisher Copyright:
Copyright © 2022 The Authors
PY - 2022/4
Y1 - 2022/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85129159019&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85129159019&partnerID=8YFLogxK
U2 - 10.1126/sciadv.abl6339
DO - 10.1126/sciadv.abl6339
M3 - Article
C2 - 35486732
AN - SCOPUS:85129159019
SN - 2375-2548
VL - 8
JO - Science Advances
JF - Science Advances
IS - 17
M1 - eabl6339
ER -