Regorafenib synergizes with TAS102 against multiple gastrointestinal cancers and overcomes cancer stemness

Sep 21, 2026

Uploaded by Maeve

Single-agent TAS102 (trifluridine/tipiracil) and regorafenib are FDA-approved therapies for metastatic colorectal cancer. The study tests the hypothesis that combining TAS102 with regorafenib may show activity across colorectal and other gastrointestinal cancers. Preclinical experiments use cell culture, colonosphere assays enriched for cancer stem cells, and in vivo xenograft models. The combination demonstrates synergistic anti-tumor effects, inhibits colonosphere formation, suppresses angiogenesis and microvessel density, and blocks TAS102-induced ERK1/2 activation largely independent of KRAS/BRAF status.

LanguageEnglish

CategoryResearch & Report

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Pages15

Reading Time38 min

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Abstract

Introduction

[www.oncotarget.com](www.oncotarget.com) Oncotarget, 2024, Vol. 15, pp: 424-438 Research Paper Regorafenib synergizes with TAS102 against multiple gastrointestinal cancers and overcomes cancer stemness, trifluridine-induced angiogenesis, ERK1/2 and STAT3 signaling regardless of KRAS or BRAF mutational status Jun Zhang 1,2,3,4,5, Lanlan Zhou 1,2,3,4,5, Shuai Zhao 1,2,3,4,5 and Wafik S . El-Deiry 1,2,3,4,5,6 1 Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA 2 Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02912, USA 3 Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02912, USA 4The Joint Program in Cancer Biology, Brown University and Lifespan Health System, RI 02912, USA 5Cancer Center at Brown University, Warren Alpert Medical School, Brown University, RI 02912, USA 6 Hematology-Oncology Division, Department of Medicine, Lifespan Health System and Warren Alpert Medical School, Brown University, RI 02912, USA Correspondence to: Wafik S. El-Deiry, [email](email: wafik@brown.edu)[: wafik@brown.edu](email: wafik@brown.edu)[ ](email: wafik@brown.edu)[Keywords](Keywords: TAS102)[: TAS102](Keywords: TAS102); regorafenib; ERK1/2; angiogenesis; microvessel density Received: May 16, 2024 Accepted: June 19, 2024 Published: July 02, 2024 Copyright: © 2024 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Single-agent TAS102 (trifluridine/tipiracil) and regorafenib are FDA-approved treatments for metastatic colorectal cancer (mCRC) . We previously reported that regorafenib combined with a fluoropyrimidine can delay disease progression in clinical case reports of multidrug-resistant mCRC patients. We hypothesized that the combination of TAS102 and regorafenib may be active in CRC and other gastrointestinal (GI) cancers and may in the future provide a treatment option for patients with advanced GI cancer. We investigated the therapeutic effect of TAS102 in combination with regorafenib in preclinical studies employing cell culture, colonosphere assays that enrich for cancer stem cells, and in vivo. TAS102 in combination with regorafenib has synergistic activity against multiple GI cancers in vitro including colorectal and gastric cancer, but not liver cancer cells. TAS102 inhibits colonosphere formation and this effect is potentiated by regorafenib. In vivo anti-tumor effects of TAS102 plus regorafenib appear to be due to anti-proliferative effects, necrosis and angiogenesis inhibition. Growth inhibition by TAS102 plus regorafenib occurs in xenografted tumors regardless of p53, KRAS or BRAF mutations, although more potent tumor suppression was observed with wild-type p53 . Regorafenib significantly inhibits TAS102-induced angiogenesis and microvessel density in xenografted tumors, as well inhibits TAS102-induced ERK1/2 activation regardless of RAS or BRAF status in vivo. TAS102 plus regorafenib is a synergistic drug combination in preclinical models of GI cancer, with regorafenib suppressing TAS102-induced increase in microvessel density and p-ERK as contributing mechanisms. The TAS102 plus regorafenib drug combination may be further tested in gastric and other GI cancers. INTRODUCTION TAS-102 is an oral formulation consisting oftrifluridine (FTD) and thymidine phosphorylase inhibitor tipiracil hydrochloride (TPI) at a molar ratio of 2:1, and is approved by the US FDA for the treatment of refractory metastatic colorectal cancer (rmCRC) and metastatic gastric cancer [1–4] . TAS102 monotherapy overcomes metastatic colorectal and gastric cancer progression failure with previous therapies [2, 4–6] . Recent studies assessed the efficacy of

FAQs

What is the main therapeutic hypothesis behind combining TAS102 with regorafenib?

The research proposes that the TAS102–regorafenib combination may be active not only in colorectal cancer but also in other gastrointestinal cancers, potentially offering a treatment option for advanced disease.

What evidence supports the synergistic effect of TAS102 and regorafenib?

Preclinical cell and in vivo experiments show synergistic anti-tumor activity across multiple gastrointestinal cancers, with increased efficacy compared with single-agent effects.

How does the combination influence angiogenesis and ERK1/2 signaling?

Regorafenib significantly inhibits TAS102-induced angiogenesis and microvessel density in xenografted tumors, and it suppresses TAS102-induced ERK1/2 activation regardless of RAS or BRAF status.

Sep 21, 2026

Uploaded by Maeve