Sorafenib targets BRAF and VEGFR in metastatic thyroid carcinoma

Abstract

6019 Background. There is no effective therapy for patients with metastatic thyroid cancer not cured by surgery or treatment with I¹³¹. Sorafenib is a promising multi-tyrosine kinase inhibitor for patients with metastatic PTC (mPTC). Although the primary targets of sorafenib are thought to include BRAF and VEGFR, this has been the subject of debate. Whether sorafenib primarily acts on the tumor cells (TC) or endothelial cells (EC) and how BRAF mutation status (45% of PTC harbor V600E) relates to response is also unknown. Methods. Responses of patients with metastatic, iodine-refractory PTC, enrolled into our phase II study of sorafenib were monitored by PET at 4 wks and CTs every 2 mos. Sorafenib activity was studied using immunohistochemistry (IHC) for pERK, pAKT, and pVEGFR-2, while Ki-67 showed proliferating cells in tumor tissue pre- and on treatment. BRAF mutation status was determined by DNA sequencing. Results. Of 15 patients, five patients achieved a PR, three are stable (SD), two progressed, and three patients with SD withdrew due to toxicity. Target lesions decreased on average 31%. Eight of 10 PET scans showed decreased activity at 4 weeks. IHC on tissue from 2 patients (at 1 and 2 wks, both BRAF^wt) showed 50% decrease in pERK (downstream of VEGFR2 and BRAF) and 30% decrease in pAKT (downstream of VEGFR2). p-ERK and p-AKT were altered in both the TC and EC. Ki-67 decreased from 10% to <1%. No change in VEGFR-2 was seen; but, pVEGFR-2 completely disappeared in one sample while the other showed a small decrease. Quantitative analysis using a multispectral imaging system confirmed the changes observed by IHC. In tissue from a patient at 17 months on sorafenib, the decrease in pERK and pAKT appeared to be the same or reversed, suggesting compensatory changes in these pathways in resistant but stable disease. Conclusions. Our study shows the early clinical and biologic activity of sorafenib in patients with mPTC and the targets of early suppression. Importantly, it also reveals compensatory changes in target molecules in cells resistant to therapy. These cells are the likely source of tumor resistance that has been seen to develop to other similar targeted agents. Sorafenib is the first viable treatment option for patients with mPTC, and these results provide key insights into the mechanisms of action and resistance of this drug. No significant financial relationships to disclose.