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Abstract
The tuberous sclerosis complex (TSC) is a rare genetic syndrome and multisystem disease resulting in tumor formation in major organs. A molecular hallmark of TSC is a dysregulation of the mammalian target of rapamycin (mTOR) through loss-of-function mutations in either tumor suppressor TSC1 or TSC2. Here, we sought to identify drug vulnerabilities conferred by TSC2 tumor-suppressor loss through cell-based chemical biology screening. Our small-molecule chemical screens reveal a sensitivity to inhibitors of checkpoint kinase 1/2 (CHK1/2), regulators of cell cycle, and DNA damage response, in both in vitro and in vivo models of TSC2-deficient renal angiomyolipoma (RA) tumors. Further, we performed transcriptional profiling on TSC2-deficient RA cell models and discovered that these recapitulate some of the features from TSC patient kidney tumors compared to normal kidneys. Taken together, our study provides a connection between mTOR-dependent tumor growth and CHK1/2, highlighting the importance of CHK1/2 inhibition as a potential antitumor strategy in TSC2-deficient tumors.
Highlights
The tuberous sclerosis complex (TSC) is a multisystem disease genetically characterized by a loss of function in either of the two tumor suppressors, TSC1 or TSC2 [1, 2]
UMB1949 cells were originally isolated from a renal angiomyolipoma and immortalized via SV40 large T antigen and hTERT introduction [18]. 105K cells were derived from a renal tumor from a Tsc2+/- mouse [19]. 621-102, 621-103, and UMB1949 were purchased from ATCC and maintained in DMEM with 10% FBS and 250 U/ml penicillin–streptomycin at 37°C with 5% CO2. 105K cells were maintained in DMEM with 10% FBS and penicillin (100 U/ml) and streptomycin (100 μg/ ml)
To identify therapeutic vulnerabilities in TSC2-deficient tumors, we used a pair of isogenic cell lines derived from a renal angiomyolipoma (RA) cell line 621-101 that were either TSC2deficient (621-102, control) or TSC2-rescued (621-103, TSC2 expression) (Figure 1A) [16]
Summary
The tuberous sclerosis complex (TSC) is a multisystem disease genetically characterized by a loss of function in either of the two tumor suppressors, TSC1 (hamartin) or TSC2 (tuberin) [1, 2]. Loss of TSC1 or TSC2 leads to constitutive activation of the mammalian target of rapamycin (mTOR) [9], a master regulator of nutrient and energy status in cells. This permits aberrant cell division and growth. Rapamycin side effects are mild to moderate, and after continuous treatment for 3 years, efficacy was maintained without new or additional significant side effects [14] Due to this cytostatic effect and favorable safety profile, most patients may require a lifelong treatment regimen of rapamycin [15]. Identifying additional therapeutic options for TSC patients that would sensitize TSC2-deficient angiomyolipoma cells might be preferable over lifelong therapy. We sought to identify new TSC2-dependent vulnerabilities using chemical biology approaches and validation in mouse models
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