Lenvatinib in combination with golvatinib overcomes hepatocyte growth factor pathway-induced resistance to vascular endothelial growth factor receptor inhibitor
Takayuki Nakagawa,Tomohiro Matsushima,Satoshi Kawano,Youya Nakazawa,Yu Kato,Yusuke Adachi,Takanori Abe,Taro Semba,Akira Yokoi,Junji Matsui,Akihiko Tsuruoka,Yasuhiro Funahashi +11 more
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TLDR
It is suggested that HGF from tumor cells confers resistance to tumor endothelial cells against VEGFR inhibitors, and that combination therapy using V EGFR inhibitors with Met inhibitors may be effective for overcoming resistance to VEGfr inhibitors.Abstract:
Vascular endothelial growth factor receptor (VEGFR) inhibitors are approved for the treatment of several tumor types; however, some tumors show intrinsic resistance to VEGFR inhibitors, and some patients develop acquired resistance to these inhibitors. Therefore, a strategy to overcome VEGFR inhibitor resistance is urgently required. Recent reports suggest that activation of the hepatocyte growth factor (HGF) pathway through its cognate receptor, Met, contributes to VEGFR inhibitor resistance. Here, we explored the effect of the HGF/Met signaling pathway and its inhibitors on resistance to lenvatinib, a VEGFR inhibitor. In in vitro experiments, addition of VEGF plus HGF enhanced cell growth and tube formation of HUVECs when compared with stimulation by either factor alone. Lenvatinib potently inhibited the growth of HUVECs induced by VEGF alone, but cells induced by VEGF plus HGF showed lenvatinib resistance. This HGF-induced resistance was cancelled when the Met inhibitor, golvatinib, was added with lenvatinib. Conditioned medium from tumor cells producing high amounts of HGF also conferred resistance to inhibition by lenvatinib. In s.c. xenograft models based on various tumor cell lines with high HGF expression, treatment with lenvatinib alone showed weak antitumor effects, but treatment with lenvatinib plus golvatinib showed synergistic antitumor effects, accompanied by decreased tumor vessel density. These results suggest that HGF from tumor cells confers resistance to tumor endothelial cells against VEGFR inhibitors, and that combination therapy using VEGFR inhibitors with Met inhibitors may be effective for overcoming resistance to VEGFR inhibitors. Further evaluation in clinical trials is warranted.read more
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Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations
Seiji Yano,Wei Wang,Qi Li,Kunio Matsumoto,Haruko Sakurama,Takahiro Nakamura,Hirokazu Ogino,Soji Kakiuchi,Masaki Hanibuchi,Yasuhiko Nishioka,Hisanori Uehara,Tetsuya Mitsudomi,Yasushi Yatabe,Toshikazu Nakamura,Saburo Sone +14 more
TL;DR: It is shown that hepatocyte growth factor (HGF), a ligand of MET oncoprotein, induces gefitinib resistance of lung adenocarcinoma cells with EGFR-activating mutations by restoring the phosphatidylinositol 3-kinase/Akt signaling pathway via phosphorylation of MET, but not EGFR or ErbB3.
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Redundant angiogenic signaling and tumor drug resistance.
TL;DR: The classical literature of such redundantAngiogenic pathways in concert with the key angiogenic factors and specialized cells involved in anti-angiogenic escape mechanisms is described and a strategic discourse regarding increasing tumor drug resistance and future modalities for anti-ANGiogenic therapy is discussed.
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Lenvatinib, a molecule with versatile application: from preclinical evidence to future development in anti-cancer treatment.
Monica Capozzi,Chiara De Divitiis,Alessandro Ottaiano,Claudia von Arx,Stefania Scala,Fabiana Tatangelo,Paolo Delrio,Salvatore Tafuto +7 more
TL;DR: An overview on lenvatinib's clinical use, perspectives and indications for future development is provided, which includes the identification of biomarkers of efficacy and resistance to len vatinib is a key challenge in order to select responsive patients.
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Design, synthesis and biological evaluation of N-phenylquinazolin-4-amine hybrids as dual inhibitors of VEGFR-2 and HDAC.
Fan-Wei Peng,Ji Xuan,Ting-Ting Wu,Jia-Yu Xue,Zi-Wei Ren,Da-Ke Liu,Xiu-Qi Wang,Xin-Hang Chen,Jia-Wei Zhang,Yungen Xu,Lei Shi +10 more
TL;DR: Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction at the active binding sites of VEGFR-2 and HDLP ((Histone Deacetylase-Like Protein), which demonstrates that compound 6fd is a potential agent for cancer therapy deserving further researching.
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MET/HGF pathway activation as a paradigm of resistance to targeted therapies.
TL;DR: In light of the failures of several earlier clinical studies of MET targeting agents, a large array of recent and current MET-focused trials are incorporating stricter patient selection and more robust predictive biomarkers providing hope for validation ofMET targeting as a clinically impactful strategy.
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