BEZ235 (PIK3/mTOR inhibitor) Overcomes Pazopanib Resistance in Patient-Derived Refractory Soft Tissue Sarcoma Cells.
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 < .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.


CONCLUSIONS
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.
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Hee Kyung
HK
Kim
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Sun Young
SY
Kim
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Su Jin
SJ
Lee
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Mihyeon
M
Kang
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Seung Tae
ST
Kim
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Jiryeon
J
Jang
Oncotest GmbH, Freiburg, Germany.
Oliver
O
Rath
Oncotest GmbH, Freiburg, Germany.
Julia
J
Schueler
Samsung Electrics, Seoul, Republic of Korea.
Dong Woo
DW
Lee
Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea; Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Woong Yang
WY
Park
Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Sung Joo
SJ
Kim
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Se Hoon
SH
Park
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address: jyunlee@skku.edu.
Jeeyun
J
Lee