Please use this identifier to cite or link to this item: https://doi.org/10.1158/1535-7163.MCT-17-0367
Title: Acquired Resistance to FGFR Inhibitor in Diffuse-Type Gastric Cancer through an AKT-Independent PKC-Mediated Phosphorylation of GSK3 beta
Authors: Lau, Wen Min 
Teng, Eileen 
Huang, Kie Kyon
Tan, Jin Wei 
Das, Kakoli 
Zang, Zhijiang 
Chia, Tania
Teh, Ming 
Kono, Koji
Yong, Wei Peng
Shabbir, Asim
Tay, Amy
Phua, Niam Sin
Tan, Patrick 
Chan, Shing Leng 
So, Jimmy Bok Yan 
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
PROTEIN-KINASE INHIBITOR
GROWTH-FACTOR RECEPTORS
SELECTIVE INHIBITOR
GENETIC ALTERATIONS
LINITIS PLASTICA
DRUG-RESISTANCE
CARCINOMA
SENSITIVITY
AMPLIFICATION
ACTIVATION
Issue Date: 1-Jan-2018
Publisher: AMER ASSOC CANCER RESEARCH
Citation: Lau, Wen Min, Teng, Eileen, Huang, Kie Kyon, Tan, Jin Wei, Das, Kakoli, Zang, Zhijiang, Chia, Tania, Teh, Ming, Kono, Koji, Yong, Wei Peng, Shabbir, Asim, Tay, Amy, Phua, Niam Sin, Tan, Patrick, Chan, Shing Leng, So, Jimmy Bok Yan (2018-01-01). Acquired Resistance to FGFR Inhibitor in Diffuse-Type Gastric Cancer through an AKT-Independent PKC-Mediated Phosphorylation of GSK3 beta. MOLECULAR CANCER THERAPEUTICS 17 (1) : 232-242. ScholarBank@NUS Repository. https://doi.org/10.1158/1535-7163.MCT-17-0367
Abstract: Preclinical models of diffuse-type gastric cancer (DGC) that reliably predict clinical activity of novel compounds are lacking. To overcome the problem of poor tumor cellularity in DGC, we used cells from malignant ascites to establish DGC patientderived xenograft (PDX) models that recapitulate the primary cancer. Cells in PDX model GAGA6 with FGFR2 amplification were sensitive to AZD4547, a potent FGFR inhibitor that is being clinically evaluated for FGFR-aberrant cancer types. Intermittent in vivo treatment of GAGA6 tumors with AZD4547 gave rise to PDX tumors with acquired resistance to AZD4547, GAGA6-R. Surprisingly, there were no mutations in the FGFR2 gene in GAGA6-R, negating gatekeeper mutations as a mechanism of drug resistance. Phosphorylation of FGFR2 and downstream signaling molecules AKT/PKB and MAPK/ERK remained inhibited by AZD4547. Further analysis of signaling pathways identified AKT-independent phosphorylation and inhibition of GSK3β as a mechanism of drug resistance in GAGA6-R cells. Treatment of GAGA6-R cells with protein kinase C (PKC) inhibitor H7 in combination with AZD4547 led to dephosphorylation and activation of GSK3β with concomitant downregulation of MCL-1 and BCL-XL. Combined treatment with AZD4547 and H7 in vitro synergistically enhanced cell death in GAGA6-R but not GAGA6 cells. Furthermore, midostaurin, a multikinase inhibitor with PKC-inhibiting activity, in part reversed resistance of GAGA6-R tumor to AZD4547 in vivo. Our results suggest that upon challenge with FGFR inhibitors, FGFR2-amplified tumors that are highly dependent on FGFR2 signaling for survival rapidly develop resistance by switching to a PKC-mediated inhibition of GSK3β to gain a survival advantage.
Source Title: MOLECULAR CANCER THERAPEUTICS
URI: https://scholarbank.nus.edu.sg/handle/10635/207796
ISSN: 15357163
15388514
DOI: 10.1158/1535-7163.MCT-17-0367
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