Table 1.

Novel therapeutic strategies based on the combination of BRAF inhibitors with other targeted agents under pre-clinical and clinical development in thyroid carcinoma.

Pre-Clinical Stage
Combined Therapy	Thyroid Cancer Subtype	Patient Number	Experimental Phase	Drug Targets	Reference
Vemurafenib + Vorinostat	BRAFV600E-mutated and wild-type TC cell lines	n.a.	in vitro	dual inhibition of BRAFV600E + histone deacetylases	[47]
Vemurafenib + Obatoclax	BRAFV600E-positive PTC cell lines, animal models	n.a.	in vitro and in vivo	dual inhibition of BRAFV600E + BCL2	[64]
Vemurafenib + Pictilisib	BRAFV600E-positive BRAFV600E/PIK3CAH1047R-mutated ATC cell lines, animal models	n.a.	in vitro and in vivo	dual inhibition of BRAFV600E + PI3K	[65]
Vemurafenib + Palbociclib	BRAFV600E-positive TC cell lines	n.a.	in vitro	dual inhibition of BRAFV600E + CDK4/6	[68]
Vemurafenib + Lapatinib	BRAFV600E-positive TC cell lines, animal models	n.a.	in vitro and in vivo	dual inhibition of BRAFV600E + HER family receptors	[69]
Vemurafenib + PHA665752	BRAFV600E-positive ATC and PTC cell lines, animal models	n.a.	in vitro and in vivo	dual inhibition of BRAFV600E + c-Met	[70]
Vemurafenib + Tocilizumab + HO-3867	BRAFV600E-positive TC cell lines and TC tissues	n.a.	in vitro	dual inhibition of BRAFV600E + IL-6 (tocilizumab) or STAT3 (HO-3867)	[71]
Vemurafenib + Gefitinib	BRAFV600E-positive PTC and ATC cell lines	n.a.	in vitro	dual inhibition of BRAFV600E + EGFR	[72,73]
Vemurafenib + Rapamycin	BRAFV600E-positive PTC and ATC cell lines	n.a.	in vitro	dual inhibition of BRAFV600E + mTOR	[74]
Vemurafenib + PD98059	BRAFV600E-positive PTC cell lines	n.a.	in vitro	dual inhibition of BRAFV600E + MEK1/2	[75]
Vemurafenib + Selumetinib	BRAFV600E- positive PTC cell lines, animal models	n.a.	in vitro and in vivo	dual inhibition of BRAFV600E + MEK1/2	[76]
Vemurafenib + Bortezomib	BRAFV600E-positive PTC and BRAFwt ATC cell lines	n.a.	in vitro	dual inhibition of BRAFV600E + proteasome	[77]
Vemurafenib + Navitoclax	BRAFV600E-positive PTC cell lines	n.a.	in vitro	dual inhibition of BRAFV600E + BCL-2/BCL-XL interaction with BIM protein	[78]
Clinical Trials
Dabrafenib + Trametinib + Everolimus	BRAFV600E- and PIK3CAH1047R-positive ATC patient	1	pre-clinical/clinical	combined inhibition of BRAFV600E + MAPK (trametinib) + mTOR (everolimus)	[79]
Dabrafenib + Trametinib + RAI	RAS/BRAFV600E-mutated metastatic RAI-refractory DTC patients	87	Phase II	potentiation of RAI activity by BRAFV600E and MEK inhibition	NCT03244956
Dabrafenib + Trametinib + IMRT	BRAFV600E-mutated ATC patients	20	Phase I	potentiation of IMRT activity by BRAFV600E/MEK inhibition	NCT03975231
Vemurafenib + RAI	TC patients	12	Pilot study	potentiation of RAI activity by BRAFV600E inhibition	NCT02145143
Dabrafenib + Lapatinib	BRAFV600E-mutated patients with unresectable/metastatic TC	21	Phase I	dual inhibition of BRAFV600E + HER family receptors	NCT01947023
Vemurafenib + KTN3379	BRAF-mutant RAI-refractory TC patients	7	Phase I	dual inhibition of BRAFV600E + HER3	NCT02456701
Vemurafenib + Atezolizumab + Cobimetinib	BRAFV600E-mutated ATC patients	50	Phase II	combined inhibition of BRAFV600E + PD-L1 (atezolizumab) + MEK (cobimetinib)	NCT03181100

n.a., not applicable.