Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF mutant thyroid carcinomas

TLDR: The HER kinase inhibitor lapatinib prevents MAPK rebound and sensitizes BRAF-mutant thyroid cancer cells to RAF or MAP-ERK kinase inhibitors, providing a rationale for combining ERK pathway antagonists with inhibitors of feedback-reactivated HER signaling in this disease.

Abstract: The RAF inhibitor vemurafenib (PLX4032) increases survival in patients with BRAF-mutant metastatic melanoma, but has limited efficacy in patients with colorectal cancers. Thyroid cancer cells are also comparatively refractory to RAF inhibitors. By contrast to melanomas, inhibition of MAPK signaling by vemurafenib is transient in thyroid and colorectal cancer cells. The rebound in ERK in thyroid cells is accompanied by increased HER3 signaling caused by induction of HER3 transcription through decreased promoter occupancy by the transcriptional repressors CtBP1 and 2, and by autocrine secretion of neuregulin-1. The HER kinase inhibitor lapatinib prevents MAPK rebound and sensitizes BRAF-mutant thyroid cancer cells to RAF or MEK inhibitors. This provides a rationale for combining ERK pathway antagonists with inhibitors of feedback-reactivated HER signaling in this disease. The determinants of primary resistance to MAPK inhibitors vary between cancer types, due to preferential upregulation of specific RTKs, and the abundance of their respective ligands.