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.

Autor: Zhang J; Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.; Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02912, USA.; Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02912, USA.; The Joint Program in Cancer Biology, Brown University and Lifespan Health System, RI 02912, USA.; Cancer Center at Brown University, Warren Alpert Medical School, Brown University, RI 02912, USA., Zhou L; Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.; Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02912, USA.; Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02912, USA.; The Joint Program in Cancer Biology, Brown University and Lifespan Health System, RI 02912, USA.; Cancer Center at Brown University, Warren Alpert Medical School, Brown University, RI 02912, USA., Zhao S; Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.; Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02912, USA.; Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02912, USA.; The Joint Program in Cancer Biology, Brown University and Lifespan Health System, RI 02912, USA.; Cancer Center at Brown University, Warren Alpert Medical School, Brown University, RI 02912, USA., El-Deiry WS; Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.; Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02912, USA.; Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02912, USA.; The Joint Program in Cancer Biology, Brown University and Lifespan Health System, RI 02912, USA.; Cancer Center at Brown University, Warren Alpert Medical School, Brown University, RI 02912, USA.; Hematology-Oncology Division, Department of Medicine, Lifespan Health System and Warren Alpert Medical School, Brown University, RI 02912, USA.
Jazyk: angličtina
Zdroj: Oncotarget [Oncotarget] 2024 Jul 02; Vol. 15, pp. 424-438. Date of Electronic Publication: 2024 Jul 02.
DOI: 10.18632/oncotarget.28602
Abstrakt: 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.
Databáze: MEDLINE
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