Targeting FGFR Pathway in Human Hepatocellular Carcinoma: Expressing pFGFR and pMET for Antitumor Activity.
The MET receptor tyrosine kinase, the receptor for hepatocyte growth factor (HGF), has been implicated in cancer growth, invasion, migration, angiogenesis, and metastasis in a broad variety of human cancers, including human hepatocellular carcinoma (HCC). Recently, MET was suggested to be a potential target for the personalized treatment of HCC with an active HGF-MET signaling pathway. However, the mechanisms of resistance to MET inhibitors need to be elucidated to provide effective treatment. Here, we show that HCC cells exhibit different sensitivities to the MET inhibitor PHA665752, depending on the phosphorylation status of FGFR. Treatment of cells expressing both phospho-FGFR and phospho-MET with the inhibitor PHA665752 did not cause growth inhibition and cell death, whereas treatment with AZD4547, a pan-FGFR inhibitor, resulted in decreased colony formation and cleavage of caspase-3. Moreover, silencing of endogenous FGFR1 and FGFR2 by RNAi of HCC cells expressing phospho-FGFR, phospho-FGFR2, and phospho-MET overcame the resistance to PHA665752 treatment. Treatment of primary cancer cells from patients with HCC expressing both phospho-FGFR and phospho-MET with PHA665752 did not induce cell death, whereas AZD4547 treatment induced cell death through the cleavage of caspase-3. In addition, treatment of cells resistant to PHA665752 with AZD4547 abrogated the activation of downstream effectors of cell growth, proliferation, and survival. On the basis of these results, we conclude that the FGFR pathway is critical for HCC survival, and that targeting this pathway with AZD4547 may be beneficial for the treatment of patients with HCC-expressing phospho-FGFR and phospho-MET.
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea.
Jae-Cheol
JC
Jo
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Eun Kyoung
EK
Choi
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Jae-Sik
JS
Shin
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Jai-Hee
JH
Moon
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Seung-Woo
SW
Hong
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. Department of Life Sciences, Sookmyung Women's University, Seoul, Republic of Korea.
Ha-Reum
HR
Lee
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Seung-Mi
SM
Kim
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Soo-A
SA
Jung
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Dae-Hee
DH
Lee
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Seang Hwan
SH
Jung
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Sun-Hye
SH
Lee
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Jeong Eun
JE
Kim
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Kyu-pyo
KP
Kim
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Yong Sang
YS
Hong
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Young-Ah
YA
Suh
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Se Jin
SJ
Jang
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Radiation Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Eun Kyung
EK
Choi
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Jung Shin
JS
Lee
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. twkimmd@amc.seoul.kr inno183@amc.seoul.kr.
Dong-Hoon
DH
Jin
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. twkimmd@amc.seoul.kr inno183@amc.seoul.kr.
Tae Won
TW
Kim
D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018613:Microscopy, Confocal; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D034622:RNA Interference; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013450:Sulfones / Q000494:pharmacology
C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; C572463:AZD4547; D000970:Antineoplastic Agents; D001549:Benzamides; D007211:Indoles; D010879:Piperazines; D011720:Pyrazoles; D013450:Sulfones; C496348:FGFR1 protein, human; C496353:FGFR2 protein, human; D019859:Proto-Oncogene Proteins c-met; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2