Pericytes Elicit Resistance to Vemurafenib and Sorafenib Therapy in Thyroid Carcinoma via the TSP-1/TGFβ1 Axis.

Abstract

PURPOSE:

The BRAFV600E oncogene modulates the papillary thyroid carcinoma (PTC) microenvironment, in which pericytes are critical regulators of tyrosine-kinase (TK)-dependent signaling pathways. Although BRAFV600E and TK inhibitors are available, their efficacy as bimodal therapeutic agents in BRAFV600E-PTC is still unknown.

EXPERIMENTAL DESIGN:

We assessed the effects of vemurafenib (BRAFV600E inhibitor) and sorafenib (TKI) as single agents or in combination in BRAFWT/V600E-PTC and BRAFWT/WT cells using cell-autonomous, pericyte coculture, and an orthotopic mouse model. We also used BRAFWT/V600E-PTC and BRAFWT/WT-PTC clinical samples to identify differentially expressed genes fundamental to tumor microenvironment.

RESULTS:

Combined therapy blocks tumor cell proliferation, increases cell death, and decreases motility via BRAFV600E inhibition in thyroid tumor cells in vitro. Vemurafenib produces cytostatic effects in orthotopic tumors, whereas combined therapy (likely reflecting sorafenib activity) generates biological fluctuations with tumor inhibition alternating with tumor growth. We demonstrate that pericytes secrete TSP-1 and TGFβ1, and induce the rebound of pERK1/2, pAKT and pSMAD3 levels to overcome the inhibitory effects of the targeted therapy in PTC cells. This leads to increased BRAFV600E-PTC cell survival and cell death refractoriness. We find that BRAFWT/V600E-PTC clinical samples are enriched in pericytes, and TSP1 and TGFβ1 expression evoke gene-regulatory networks and pathways (TGFβ signaling, metastasis, tumor growth, tumor microenvironment/ECM remodeling functions, inflammation, VEGF ligand-VEGF receptor interactions, immune modulation, etc.) in the microenvironment essential for BRAFWT/V600E-PTC cell survival. Critically, antagonism of the TSP-1/TGFβ1 axis reduces tumor cell growth and overcomes drug resistance.

CONCLUSIONS:

Pericytes shield BRAFV600E-PTC cells from targeted therapy via TSP-1 and TGFβ1, suggesting this axis as a new therapeutic target for overcoming resistance to BRAFV600E and TK inhibitors.

• Authors: Alessandro Prete, Agnes S Lo, Peter M Sadow, Swati S Bhasin, Zeus A Antonello, Danica M Vodopivec, Soumya Ullas, Jennifer N Sims, John Clohessy, Ann M Dvorak, Tracey Sciuto, Manoj Bhasin, Joanne E Murphy-Ullrich, Jack Lawler, S Ananth Karumanchi, Carmelo Nucera
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 24 Issue 23 Pg. 6078-6097 (12 01 2018) ISSN: 1557-3265 [Electronic] United States
• PMID: 30076136 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• Biomarkers, Tumor
• SPZ1 protein, human
• TGFB1 protein, human
• Transforming Growth Factor beta1
• Vemurafenib
• Sorafenib

Topics

• Animals
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (genetics, metabolism)
• Biomarkers, Tumor
• Cell Line, Tumor
• Disease Models, Animal
• Drug Resistance, Neoplasm (genetics)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Models, Biological
• Pericytes (drug effects, metabolism)
• Signal Transduction (drug effects)
• Sorafenib (pharmacology)
• Thyroid Neoplasms (drug therapy, genetics, metabolism, pathology)
• Transforming Growth Factor beta1 (genetics, metabolism)
• Tumor Microenvironment (drug effects, genetics)
• Vemurafenib (pharmacology)
• Xenograft Model Antitumor Assays