BRAF inhibitors: experience in thyroid cancer and general review of toxicity

Abstract

The US Food and Drug Administration-approved BRAF inhibitors, vemurafenib and dabrafenib, have demonstrated superior efficacy in patients with BRAF-mutant melanomas but have limited efficacy in BRAF-mutant colorectal cancer. Little is known at this time regarding BRAF inhibitors in thyroid cancer. Initial reports in patients with progressive, radioactive iodine-refractory BRAF-mutant papillary thyroid cancer suggest response rates of approximately 30-40%. In this review, we discuss BRAF inhibitors in the context of thyroid cancer, the toxicities associated with BRAF inhibitors, and the suggested management of those toxicities. The management of vemurafenib and dabrafenib toxicities is applicable across all tumor types and may serve as a practical guide to their use.

Fig. 1

Mechanisms of selective B-Raf (V600E) inhibitor resistance. a In melanoma and colon cancer, cells are known to acquire resistance to B-Raf (V600E) inhibitors through several mechanisms. The RAS-RAF-MEK-ERK or PI3K-AKT pathways can be driven by (1) upregulation or activation of receptor tyrosine kinases (RTK) such as IGF-1R, PDGFRβ, and EGFR or (2) acquired RAS-activating mutations. (3) BRAF splice variants with truncated RAS binding domains permit RAS-independent activator-receiver dimerization. (4) RAS-dependent transactivation of RAF receivers (BRAF or CRAF) by inhibitor-bound wild-type BRAF or CRAF activators. (5) Acquired MEK-activating mutations can act on ERK1/2 independently of RAS and RAF activity. (6) Increased activity of downstream kinases, such as COT, can bypass the inhibition of BRAF and directly phosphorylate MEK. b In papillary thyroid cancer, a mechanism of resistance has been demonstrated through neuregulin-1 (NRG1)-dependent activation of HER2/HER3. Activation of HER2/HER3 then drives both the RAS-RAF-MEK-ERK and/or PI3K-AKT pathways

Fig. 2

Examples of skin toxicities: a keratosis pilaris-like eruptions, b hyperkeratotic punctate lesion on the hand, c verrucous keratoses, and d melanocytic nevi