Abstract
Inactivating mutations in either TSC1 or TSC2 cause Tuberous Sclerosis Complex, an autosomal dominant disorder, characterized by multi-system tumor and hamartoma development. Mutation and loss of function of TSC1 and/or TSC2 also occur in a variety of sporadic cancers, and rapamycin and related drugs show highly variable treatment benefit in patients with such cancers. The TSC1 and TSC2 proteins function in a complex that inhibits mTORC1, a key regulator of cell growth, which acts to enhance anabolic biosynthetic pathways. In this study, we identified and validated five cancer cell lines with TSC1 or TSC2 mutations and performed a kinase inhibitor drug screen with 197 compounds. The five cell lines were sensitive to several mTOR inhibitors, and cell cycle kinase and HSP90 kinase inhibitors. The IC50 for Torin1 and INK128, both mTOR kinase inhibitors, was significantly increased in three TSC2 null cell lines in which TSC2 expression was restored. Rapamycin was significantly more effective than either INK128 or ganetespib (an HSP90 inhibitor) in reducing the growth of TSC2 null SNU-398 cells in a xenograft model. Combination ganetespib-rapamycin showed no significant enhancement of growth suppression over rapamycin. Hence, although HSP90 inhibitors show strong inhibition of TSC1/TSC2 null cell line growth in vitro, ganetespib showed little benefit at standard dosage in vivo. In contrast, rapamycin which showed very modest growth inhibition in vitro was the best agent for in vivo treatment, but did not cause tumor regression, only growth delay.
Highlights
Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder, which is caused by inactivating mutation either in TSC1 or TSC2
Identification of Hsp90 inhibitors as potential drugs for the treatment of TSC1/TSC2 deficient cancer were reported to have mutations in TSC1 and 111 to have mutations in TSC2. These mutations were reviewed to identify those with nonsense mutations, frameshift deletions or insertions, or in-frame deletions in either TSC1 or TSC2, yielding 4 cell lines with probable mutations in TSC1 and 10 with probable mutations in TSC2 (Table 1)
Given the evidence of some synergy in the growth inhibition of the TSC1/TSC2 null cell lines in response to combined mechanistic target of rapamycin (mTOR) and Heat shock protein 90 (HSP90) inhibition, and evidence that they were impacting growth through different mechanisms, we explored the potential synergistic effect of treatment with these compounds in vivo using a subcutaneous xenograft tumor model with SNU-398 cells. 3.0x106 SNU-398 cells were injected subcutaneously into the flank region of immunodeficient
Summary
Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder, which is caused by inactivating mutation either in TSC1 or TSC2. Mutations in either gene cause the same phenotype, mutations in TSC1 are associated with milder clinical severity in multiple respects [1, 2]. There are multiple highly specific clinical features of TSC including cortical tubers, subependymal nodules, cardiac rhabdomyoma, kidney angiomyolipoma, pulmonary lymphangioleiomyomatosis, facial and ungual angiofibromas [1,2,3,4]. Inactivating TSC1 and TSC2 mutations occur rarely in multiple cancer types. Cancers with higher rates of TSC1/TSC2 mutation include: urothelial carcinoma of the bladder and upper tract, with 6–10% incidence of TSC1 mutations [5] and perivascular epithelioid cell tumors (PEComa) with up to 50% frequency of TSC2 and TSC1 mutations [6]
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