BEZ235 (PIK3/mTOR inhibitor) overcomes pazopanib resistance in patient-derived refractory soft tissue sarcoma cells

Hee Kyung Kim, Sun Young Kim, Su Jin Lee, Mihyeon Kang, Seung Tae Kim, Jiryeon Jang, Oliver Rath, Julia Schueler, Dong Woo Lee, Woong Yang Park, Sung Joo Kim, Se Hoon Park, Jeeyun Lee

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

BACKGROUND: Although pazopanib treatment has become the standard chemotherapy in salvage setting for metastatic sarcoma patients, most patients progress after pazopanib treatment in 4 to 6 months. After failure to pazopanib, patients have limited options for treatment. Therefore, subsequent therapy in patients who failed to pazopanib is urgently needed and the use of patient derived cells or patient derived tumors for accompanying testing with various pharmacological inhibitors could offer additional treatment options for these patients. METHODS: Patient derived tumor cells were collected from ascites at the time of progression to pazopanib and a 13-drug panel was tested for drug sensitivity. We confirmed the results using in vitro cell viability assay and immunoblot assay. We also performed the genomic profiling of PDX model. RESULTS: The growth of patient derived tumor cells was significantly reduced by exposure to 1.0 μM AZD2014 compared with control (control versus AZD2014, mean growth = 100.0% vs 16.04%, difference = 83.96%, 95% CI = 70.01% to 97.92%, P =.0435). Similarly, 1.0 μM BEZ235 profoundly inhibited tumor cell growth in vitro when compared to control (control versus BEZ235, mean growth = 100.0% vs 7.308%, difference = 92.69%, 95% CI = 78.87% to 106.5%, P b.0001). Despite the presence of CDK4 amplification in the patient-derived tumor cells, LEE011 did not considerably inhibit cell proliferation when compared with control (control vs LEE011, mean growth = 100.0% vs 80.23%, difference = 19.77%, 95% CI = 1.828% to 37.72%, P =.0377). The immunoblot analysis showed that BEZ235 treatment decreased pAKT, pmTOR and pERK whereas AZD2014 decreased only pmTOR. CONCLUSION: Taken together, upregulation of mTOR/AKT pathway in sarcoma patient derived cells was considerably inhibited by the treatment of AZD2014 and BEZ235 with downregulation of AKT pathway (greater extent for BEZ235). These molecules may be considered as treatment option in STS patient who have failed to pazopanib in the context of clinical trials.

Original languageEnglish
Pages (from-to)197-202
Number of pages6
JournalTranslational Oncology
Volume9
Issue number3
DOIs
StatePublished - 1 Jun 2016

Bibliographical note

Funding Information:
This work was supported by a grant from the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI14C0072, HI14C3418, HI14C2750). Support was also provided by a grant from the 20 by 20 project of Samsung Medical Center (GF01160111) and the Samsung Medical Center (SMX1161251).

Publisher Copyright:
© 2016 The Authors.

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