Transcriptomics-Based Drug Repurposing Approach Identifies Novel Drugs against Sorafenib-Resistant Hepatocellular Carcinoma.
Transcriptomics-Based Drug Repurposing Approach Identifies Novel Drugs against Sorafenib-Resistant Hepatocellular Carcinoma.
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DOI：
10.3390/cancers12102730
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发表时间：
2020-09-23
期刊：
影响因子：
5.2
通讯作者：
Motiwala T
中科院分区：
文献类型：
--
作者：
Regan-Fendt K;Li D;Reyes R;Yu L;Wani NA;Hu P;Jacob ST;Ghoshal K;Payne PRO;Motiwala T
Hepatocellular carcinoma (HCC), a type of liver cancer, remains a treatment challenge due to late detection and resistance to currently approved drugs. It takes 15–20 years for a single new drug to become FDA approved. The purpose of this study was to expedite identification of novel drugs against drug-resistant HCC. For this, we matched gene expression alterations in resistant HCC with gene expression changes caused by treatment of cancer cells with drugs already FDA approved for other diseases to find the drug that can reverse the resistance-related changes. Among the identified drugs, we validated the growth inhibitory effect of two drugs, identified their mechanism in HCC and, thus, provided proof of concept evidence for validity of this drug repurposing approach with potential for use in personalized medicine. Objective: Hepatocellular carcinoma (HCC) is frequently diagnosed in patients with late-stage disease who are ineligible for curative surgical therapies. The majority of patients become resistant to sorafenib, the only approved first-line therapy for advanced cancer, underscoring the need for newer, more effective drugs. The purpose of this study is to expedite identification of novel drugs against sorafenib resistant (SR)-HCC. Methods: We employed a transcriptomics-based drug repurposing method termed connectivity mapping using gene signatures from in vitro-derived SR Huh7 HCC cells. For proof of concept validation, we focused on drugs that were FDA-approved or under clinical investigation and prioritized two anti-neoplastic agents (dasatinib and fostamatinib) with targets associated with HCC. We also prospectively validated predicted gene expression changes in drug-treated SR Huh7 cells as well as identified and validated the targets of Fostamatinib in HCC. Results: Dasatinib specifically reduced the viability of SR-HCC cells that correlated with up-regulated activity of SRC family kinases, its targets, in our SR-HCC model. However, fostamatinib was able to inhibit both parental and SR HCC cells in vitro and in xenograft models. Ingenuity pathway analysis of fostamatinib gene expression signature from LINCS predicted JAK/STAT, PI3K/AKT, ERK/MAPK pathways as potential targets of fostamatinib that were validated by Western blot analysis. Fostamatinib treatment reversed the expression of genes that were deregulated in SR HCC. Conclusion: We provide proof of concept evidence for the validity of this drug repurposing approach for SR-HCC with implications for personalized medicine.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
11.5
作者：
Guo, Weixing;Liu, Shupeng;Liu, Shanrong
通讯作者：
Liu, Shanrong
影响因子：
3.7
作者：
Chen MH;Yang WL;Lin KT;Liu CH;Liu YW;Huang KW;Chang PM;Lai JM;Hsu CN;Chao KM;Kao CY;Huang CY
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Huang CY
Beegle：从文献挖掘到疾病基因发现。
影响因子：
14.9
作者：
ElShal S;Tranchevent LC;Sifrim A;Ardeshirdavani A;Davis J;Moreau Y
通讯作者：
Moreau Y
影响因子：
28.4
作者：
Global Burden of Disease Cancer Collaboration;Fitzmaurice C;Allen C;Barber RM;Barregard L;Bhutta ZA;Brenner H;Dicker DJ;Chimed-Orchir O;Dandona R;Dandona L;Fleming T;Forouzanfar MH;Hancock J;Hay RJ;Hunter-Merrill R;Huynh C;Hosgood HD;Johnson CO;Jonas JB;Khubchandani J;Kumar GA;Kutz M;Lan Q;Larson HJ;Liang X;Lim SS;Lopez AD;MacIntyre MF;Marczak L;Marquez N;Mokdad AH;Pinho C;Pourmalek F;Salomon JA;Sanabria JR;Sandar L;Sartorius B;Schwartz SM;Shackelford KA;Shibuya K;Stanaway J;Steiner C;Sun J;Takahashi K;Vollset SE;Vos T;Wagner JA;Wang H;Westerman R;Zeeb H;Zoeckler L;Abd-Allah F;Ahmed MB;Alabed S;Alam NK;Aldhahri SF;Alem G;Alemayohu MA;Ali R;Al-Raddadi R;Amare A;Amoako Y;Artaman A;Asayesh H;Atnafu N;Awasthi A;Saleem HB;Barac A;Bedi N;Bensenor I;Berhane A;Bernabé E;Betsu B;Binagwaho A;Boneya D;Campos-Nonato I;Castañeda-Orjuela C;Catalá-López F;Chiang P;Chibueze C;Chitheer A;Choi JY;Cowie B;Damtew S;das Neves J;Dey S;Dharmaratne S;Dhillon P;Ding E;Driscoll T;Ekwueme D;Endries AY;Farvid M;Farzadfar F;Fernandes J;Fischer F;G/Hiwot TT;Gebru A;Gopalani S;Hailu A;Horino M;Horita N;Husseini A;Huybrechts I;Inoue M;Islami F;Jakovljevic M;James S;Javanbakht M;Jee SH;Kasaeian A;Kedir MS;Khader YS;Khang YH;Kim D;Leigh J;Linn S;Lunevicius R;El Razek HMA;Malekzadeh R;Malta DC;Marcenes W;Markos D;Melaku YA;Meles KG;Mendoza W;Mengiste DT;Meretoja TJ;Miller TR;Mohammad KA;Mohammadi A;Mohammed S;Moradi-Lakeh M;Nagel G;Nand D;Le Nguyen Q;Nolte S;Ogbo FA;Oladimeji KE;Oren E;Pa M;Park EK;Pereira DM;Plass D;Qorbani M;Radfar A;Rafay A;Rahman M;Rana SM;Søreide K;Satpathy M;Sawhney M;Sepanlou SG;Shaikh MA;She J;Shiue I;Shore HR;Shrime MG;So S;Soneji S;Stathopoulou V;Stroumpoulis K;Sufiyan MB;Sykes BL;Tabarés-Seisdedos R;Tadese F;Tedla BA;Tessema GA;Thakur JS;Tran BX;Ukwaja KN;Uzochukwu BSC;Vlassov VV;Weiderpass E;Wubshet Terefe M;Yebyo HG;Yimam HH;Yonemoto N;Younis MZ;Yu C;Zaidi Z;Zaki MES;Zenebe ZM;Murray CJL;Naghavi M
通讯作者：
Naghavi M