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Article: Overriding adaptive resistance to sorafenib via combination therapy with SHP2 blockade in hepatocellular carcinoma

TitleOverriding adaptive resistance to sorafenib via combination therapy with SHP2 blockade in hepatocellular carcinoma
Authors
KeywordsHCC
RTK
SHP2
sorafenib
Issue Date2020
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/
Citation
Hepatology, 2020, v. 72 n. 1, p. 155-168 How to Cite?
AbstractThe survival benefit of sorafenib for hepatocellular carcinoma (HCC) patients is unsatisfactory due to the development of adaptive resistance. Increasing evidence has demonstrated that drug resistance can be acquired by cancer cells by activating a number of signaling pathways via receptor tyrosine kinases (RTKs), nevertheless the detailed mechanism for the activation of these alternative pathways is not fully understood. Given the physiological role of Src‐homology 2 domain–containing phosphatase 2 (SHP2) as a downstream effector of many RTKs for activation various signaling cascades, we first found that SHP2 was markedly upregulated in our established sorafenib‐resistant cell lines as well as patient‐derived xenograft (PDTX). Upon sorafenib treatment, adaptive resistance was acquired in HCC cells via activation of RTKs including AXL, EGFR, EPHA2 and IGF1R, leading to RAS/MEK/ERK and AKT reactivation. We found that SHP2 inhibitor SHP099 abrogated sorafenib resistance in HCC cell lines and organoid culture in vitro by blocking this negative feedback mechanism. Interestingly, this sensitization effect was also mediated by induction of cellular senescence. SHP099 in combination with sorafenib was highly efficacious in the treatment of xenografts and genetically engineered models of HCC. In conclusion, SHP2 blockade by SHP099 in combination with sorafenib attenuated the adaptive resistance to sorafenib by impeding RTK‐induced reactivation of the MEK/ERK and AKT signaling pathways. SHP099 in combination with sorafenib may be a novel and safe therapeutic strategy against HCC.
Persistent Identifierhttp://hdl.handle.net/10722/278926
ISSN
2019 Impact Factor: 14.679
2015 SCImago Journal Rankings: 4.752

 

DC FieldValueLanguage
dc.contributor.authorLeung, CON-
dc.contributor.authorTong, M-
dc.contributor.authorChung, KPS-
dc.contributor.authorZhou, L-
dc.contributor.authorCHE, N-
dc.contributor.authorTang, KH-
dc.contributor.authorDing, J-
dc.contributor.authorLau, EYT-
dc.contributor.authorNg, IOL-
dc.contributor.authorMa, S-
dc.contributor.authorLee, TKW-
dc.date.accessioned2019-10-21T02:16:28Z-
dc.date.available2019-10-21T02:16:28Z-
dc.date.issued2020-
dc.identifier.citationHepatology, 2020, v. 72 n. 1, p. 155-168-
dc.identifier.issn0270-9139-
dc.identifier.urihttp://hdl.handle.net/10722/278926-
dc.description.abstractThe survival benefit of sorafenib for hepatocellular carcinoma (HCC) patients is unsatisfactory due to the development of adaptive resistance. Increasing evidence has demonstrated that drug resistance can be acquired by cancer cells by activating a number of signaling pathways via receptor tyrosine kinases (RTKs), nevertheless the detailed mechanism for the activation of these alternative pathways is not fully understood. Given the physiological role of Src‐homology 2 domain–containing phosphatase 2 (SHP2) as a downstream effector of many RTKs for activation various signaling cascades, we first found that SHP2 was markedly upregulated in our established sorafenib‐resistant cell lines as well as patient‐derived xenograft (PDTX). Upon sorafenib treatment, adaptive resistance was acquired in HCC cells via activation of RTKs including AXL, EGFR, EPHA2 and IGF1R, leading to RAS/MEK/ERK and AKT reactivation. We found that SHP2 inhibitor SHP099 abrogated sorafenib resistance in HCC cell lines and organoid culture in vitro by blocking this negative feedback mechanism. Interestingly, this sensitization effect was also mediated by induction of cellular senescence. SHP099 in combination with sorafenib was highly efficacious in the treatment of xenografts and genetically engineered models of HCC. In conclusion, SHP2 blockade by SHP099 in combination with sorafenib attenuated the adaptive resistance to sorafenib by impeding RTK‐induced reactivation of the MEK/ERK and AKT signaling pathways. SHP099 in combination with sorafenib may be a novel and safe therapeutic strategy against HCC.-
dc.languageeng-
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/-
dc.relation.ispartofHepatology-
dc.rightsPreprint This is the pre-peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Postprint This is the peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.-
dc.subjectHCC-
dc.subjectRTK-
dc.subjectSHP2-
dc.subjectsorafenib-
dc.titleOverriding adaptive resistance to sorafenib via combination therapy with SHP2 blockade in hepatocellular carcinoma-
dc.typeArticle-
dc.identifier.emailTong, M: caroltm@hku.hk-
dc.identifier.emailZhou, L: lenazhou@connect.hku.hk-
dc.identifier.emailNg, IOL: iolng@hku.hk-
dc.identifier.emailMa, S: stefma@hku.hk-
dc.identifier.authorityTong, M=rp02568-
dc.identifier.authorityNg, IOL=rp00335-
dc.identifier.authorityMa, S=rp00506-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/hep.30989-
dc.identifier.scopuseid_2-s2.0-85082568872-
dc.identifier.hkuros308140-
dc.identifier.volume72-
dc.identifier.issue1-
dc.identifier.spage155-
dc.identifier.epage168-
dc.publisher.placeUnited States-

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