The preclinical development of regorafenib for the treatment of colorectal cancer

Miura, Koh; Satoh, Masayuki; Kinouchi, Makoto; Yamamoto, Kuniharu; Hasegawa, Yasuhiro; Philchenkov, Alex; Kakugawa, Yoichiro; Fujiya, Tsuneaki

doi:10.1517/17460441.2014.924923

Cited by 32 publications

(30 citation statements)

References 51 publications

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“…38 Sorafenib and regorafenib, which are being evaluated in phase III trials, have shown partial activity against this pathway. 50,51 The PI3K/AKT/mTOR pathway controls cell survival, as well as proliferation and cellcycle regulation. This pathway is activated by various tyrosine kinase receptors, such as EGFR or insulinlike growth factor receptor 1 (IGFR), and by inactivation of the tumour suppressor phosphatase and tensin homo logue (PTEN).…”

Section: Signalling Pathwaysmentioning

confidence: 99%

Advances in targeted therapies for hepatocellular carcinoma in the genomic era

et al. 2015

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Mortality owing to liver cancer has increased in the past 20 years, and the latest estimates indicate that the global health burden of this disease will continue to grow. Most patients with hepatocellular carcinoma (HCC) are still diagnosed at intermediate or advanced disease stages, where curative approaches are often not feasible. Among the treatment options available, the molecular targeted agent sorafenib is able to significantly increase overall survival in these patients. Thereafter, up to seven large, randomized phase III clinical trials investigating other molecular therapies in the first-line and second-line settings have failed to improve on the results observed with this agent. Potential reasons for this include intertumour heterogeneity, issues with trial design and a lack of predictive biomarkers of response. During the past 5 years, substantial advances in our knowledge of the human genome have provided a comprehensive picture of commonly mutated genes in patients with HCC. This knowledge has not yet influenced clinical decision-making or current clinical practice guidelines. In this Review the authors summarize the molecular concepts of progression, discuss the potential reasons for clinical trial failure and propose new concepts of drug development, which might lead to clinical implementation of emerging targeted agents.

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Section: Signalling Pathwaysmentioning

confidence: 99%

Advances in targeted therapies for hepatocellular carcinoma in the genomic era

et al. 2015

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“…The current standard treatment for patients with CRC is surgical resection followed by chemotherapy, e.g., the combination of 5-fluorouracil, oxaliplatin and irinotecan for those patients; however, resistance to chemotherapy remains a major problem in the treatment of this disease because continuous chemotherapy with or without a targeting drug inevitably induces toxicity to normal tissues [2-4]. Despite considerable advances in the treatment of CRC, substantial changes in treatment strategies are required to overcome these problems of drug resistance and toxicity.…”

Section: Introductionmentioning

confidence: 99%

HSP90 inhibitor NVP-AUY922 enhances TRAIL-induced apoptosis by suppressing the JAK2-STAT3-Mcl-1 signal transduction pathway in colorectal cancer cells

Lee

Sung

Bartlett

et al. 2015

Cellular Signalling

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TRAIL has been shown to induce apoptosis in cancer cells, but in some cases certain cancer cells are resistant to this ligand. In this study, we explored the ability of representative HSP90 (heat shock protein 90) inhibitor NVP-AUY922 to overcome TRAIL resistance by increasing apoptosis in colorectal cancer (CRC) cells. The combination of TRAIL and NVP-AUY922 induced synergistic cytotoxicity and apoptosis, which was mediated through an increase in caspase activation. The treatment of NVP-AUY922 dephosphorylated JAK2 and STAT3 and decreased Mcl-1 which resulted in facilitating cytochrome c release. NVP-AUY922-mediated inhibition of JAK2/STAT3 signaling and down-regulation of their target gene, Mcl-1, occurred in a dose and time-dependent manner. Knock down of Mcl-1, STAT3 inhibitor or JAK2 inhibitor synergistically enhanced TRAIL-induced apoptosis. Taken together, our results suggest the involvement of the JAK2-STAT3-Mcl-1 signal transduction pathway in response to NVP-AUY922 treatment, which may play a key role in NVP-AUY922-mediated sensitization to TRAIL. In contrast, the effect of the combination treatments in non-transformed colon cells was minimal. We provide a clinical rationale that combining HSP90 inhibitor with TRAIL enhances therapeutic efficacy without increasing normal tissue toxicity in CRC patients.

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Section: Introductionmentioning

confidence: 99%

“…Regorafenib (BAY 73‐4306) is an orally bioavailable, small‐molecule multikinase inhibitor of VEGFR1‐3, TIE2, PDGFR‐β, FGFR, KIT, RET, and BRAF (Miura et al ., ; Wilhelm et al ., ). As efficacy and safety were demonstrated in colorectal cancers and gastrointestinal stromal tumors (GISTs), regorafenib was recently approved for the treatment of patients with metastatic colorectal cancer and advanced GIST by the FDA in 2012 (Miura et al ., ). Clinical trials assessing regorafenib in the treatment of gastric cancer, colorectal cancer, renal cell carcinoma, and hepatocellular carcinoma are underway as monotherapy as well as in combination with other chemotherapeutic agents such as 5‐fluorouracil, oxaliplatin, and irinotecan (Bruix et al ., ; Eisen et al ., ; Li et al ., ; Pavlakis et al ., ).…”

Section: Introductionmentioning

confidence: 99%

FGFR2 amplification is predictive of sensitivity to regorafenib in gastric and colorectal cancers in vitro

et al. 2018

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Although regorafenib has demonstrated survival benefits in patients with metastatic colorectal and gastrointestinal stromal tumors, no proven biomarker has been identified for predicting sensitivity to regorafenib. Here, we investigated preclinical activity of regorafenib in gastric and colorectal cancer cells to identify genetic alterations associated with sensitivity to regorafenib. Mutation profiles and copy number assays of regorafenib target molecules indicated that amplification of fibroblast growth factor receptor 2 (FGFR2) was the only genetic alteration associated with in vitro sensitivity to regorafenib. Regorafenib effectively inhibited phosphorylation of FGFR2 and its downstream signaling molecules in a dose‐dependent manner and selectively in FGFR2‐amplified cells. Regorafenib induced G1 arrest (SNU‐16, KATO‐III) and apoptosis (NCI‐H716); however, no significant changes were seen in cell lines without FGFR2 amplification. In SNU‐16 mice xenografts, regorafenib significantly inhibited tumor growth, proliferation, and FGFR signaling compared to treatment with control vehicle. Regorafenib effectively abrogates activated FGFR2 signaling in FGFR2‐amplified gastric and colorectal cancer and, therefore, might be considered for integration into treatment in patients with FGFR2‐amplified gastric and colorectal cancers.

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The preclinical development of regorafenib for the treatment of colorectal cancer

Cited by 32 publications

References 51 publications

Advances in targeted therapies for hepatocellular carcinoma in the genomic era

Advances in targeted therapies for hepatocellular carcinoma in the genomic era

HSP90 inhibitor NVP-AUY922 enhances TRAIL-induced apoptosis by suppressing the JAK2-STAT3-Mcl-1 signal transduction pathway in colorectal cancer cells

FGFR2 amplification is predictive of sensitivity to regorafenib in gastric and colorectal cancers in vitro

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