Inhibition of BRAF and ERK1/2 has synergistic effects on thyroid cancer growth in vitro and in vivo

Abstract

Mutations in the BRAF gene are highly prevalent in thyroid cancer. However, the response rate of thyroid tumors to BRAF‐directed therapies has been mixed. Increasingly, combination therapies inhibiting the MAPK pathway at multiple nodes have shown promise. Recently developed ERK1/2 inhibitors are of interest for use in combination therapies as they have the advantage of inhibiting the most downstream node of the MAPK pathway, therefore preventing pathway reactivation. Here, we examined the effect of combined BRAF inhibition (dabrafenib) and ERK1/2 inhibition (SCH772984) on the growth and survival of a panel of BRAF‐mutant thyroid cancer cell lines using in vitro and in vivo approaches. We found that resistance due to MAPK pathway reactivation occurs quickly with single‐agent BRAF inhibition, but can be prevented with combined BRAF and ERK1/2 inhibition. Combined inhibition also results in synergistic growth inhibition, decreased clonogenic survival, and enhanced induction of apoptosis in a subset of BRAF‐mutant thyroid cancer cells. Finally, combined inhibition of BRAF and ERK1/2 results in enhanced inhibition of tumor growth in an anaplastic thyroid cancer in vivo model. These results provide key rationale to pursue combined BRAF and ERK1/2 inhibition as an alternative therapeutic strategy for BRAF‐mutant advanced thyroid cancer patients.

Selective Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibition by the SCH772984 Compound Attenuates In Vitro and In Vivo Inflammatory Responses and Prolongs Survival in Murine Sepsis Models

“…Several studies have shown that SCH772984 inhibited BRAF/RAS-mutant cancer cells proliferation and increased apoptosis in vitro and in vivo [ 23 , 46 , 47 , 48 ]. Furthermore, a combination of SCH772984 with other anticancer drugs, including Cucurbitacin B [ 49 ] and dabrafenib [ 50 ], had a synergistic effect on tumor growth inhibition in pancreatic and thyroid cancer in vivo models, respectively. Apart from oncology, Wong and colleagues have used a combination of siRNA knockdown and SCH772984 to define the role of LPS-induced ERK activation in primary human endothelial cells.…”

Downregulation of cellular retinoic acid binding protein 1 fosters epithelial–mesenchymal transition in thyroid cancer

“…40 associated with increased cell proliferation. 41 The neutral effects of CRABP1 modulation on cell growth and cell cycle progression in this study may be explained by counteracting effects from other signaling pathways, such as Akt attenuation. Although modulating EGFR signaling did not alter cell growth in this study, the corresponding change affected the invasive ability of thyroid cancer cells.…”

miR‐506‐loaded gelatin nanospheres target PENK and inactivate the ERK/Fos signaling pathway to suppress triple‐negative breast cancer aggressiveness

“…PENK and its hydrolysates could also inhibit tumor progression 28 . It has been confirmed that AP‐1 proteins, especially Fos family members, might play an important role in the invasion of breast cancer cells through forming dimers with Jun, and then bond to the regulatory sequences of target genes 39,40,53–55 . Knockdown of Fos reversed p38 activation induced by interleukin‐1β and promoted metastasis of gastric adenocarcinoma and inflammation‐mediated skin tumorigenesis 56 .…”

“…28 It has been confirmed that AP-1 proteins, especially Fos family members, might play an important role in the invasion of breast cancer cells through forming dimers with Jun, and then bond to the regulatory sequences of target genes. 39,40,[53][54][55] Knockdown of Fos reversed p38 activation induced by interleukin-1β and promoted metastasis of gastric adenocarcinoma and inflammation-mediated skin tumorigenesis. 56 Inactivation of the ERK/Fos signaling pathway strongly suppressed the growth of cervical cancer cells and promoted apoptosis.…”