Checkpoint kinase (CHK1/2) inhibitors may offer a promising new treatment strategy for kidney tumors associated with tuberous sclerosis complex (TSC). In a recent study, researchers found that TSC2-deficient renal angiomyolipoma cells are highly sensitive to CHK1/2 inhibition. These findings were reached in part with the support of the TSC Alliance Preclinical Consortium. In multiple mouse models, treatment with the dual CHK1/2 inhibitor AZD7762 significantly reduced tumor volume and caused complete tumor stasis, meaning tumor growth stopped entirely. The drug also reduced kidney cystadenomas and slowed disease progression in a genetically engineered mouse model of TSC.
TSC, a rare genetic disorder, is characterized by the formation of tumors in various organs, including the kidneys. A key molecular feature of TSC is the dysregulation of the mammalian target of rapamycin (mTOR) pathway due to mutations in either the TSC1 or TSC2 tumor suppressor genes. Renal angiomyolipomas (RA) are the most common kidney lesions in TSC patients, often requiring lifelong surveillance due to the risk of spontaneous hemorrhage. Current treatments, such as rapamycin (sirolimus) and its analogs, target the mTOR pathway and can reduce tumor volume, but their effects only shrink or stabilize tumor growth, meaning tumors can regrow if treatment is stopped. This highlights the need for additional therapeutic options that could offer more sustained or curative effects.
The study aimed to find new drug vulnerabilities in TSC2-deficient tumors, which represent the majority of TSC cases. Researchers used cell-based chemical biology screening on TSC2-deficient renal angiomyolipoma cells. They compared the effects of various compounds on TSC2-deficient cells against TSC2-rescued cells (which have normal TSC2 function). The screens revealed that TSC2-deficient cells were particularly sensitive to inhibitors of checkpoint kinase 1/2 (CHK1/2). These kinases are crucial regulators of the cell cycle and the DNA damage response. Two specific CHK1/2 inhibitors, LY2603618 and AZD7762, were identified as selectively potent against TSC2-deficient cells. AZD7762, a dual CHK1/2 inhibitor, showed even greater potency compared to the more selective CHK1 inhibitor, LY2603618.
To validate these findings, the researchers tested the dual CHK1/2 inhibitor AZD7762 in several mouse models of TSC2-deficient tumors. In a cell line tumor-graft model using patient-derived UMB1949 cells, AZD7762 treatment significantly reduced tumor size and led to complete tumor stasis, meaning the tumors stopped growing entirely. This effect was confirmed by observing decreased phosphorylation of CHK1, indicating successful target inhibition. Similar results were found in two additional mouse models in collaboration with the Preclinical Consortium. Using tumor-graft 105K cells, another Tsc2-deficient cystadenoma cell line, AZD7762 treatment also led to a significant reduction in tumor volume and complete tumor stasis. Also, in a genetically engineered mouse model (A/J Tsc2+/-) that spontaneously develops kidney pathology, AZD7762 treatment reduced cystadenomas and slowed the progression from cysts to more severe cystadenomas.
These discoveries suggest that targeting CHK1/2 could offer a more effective and potentially curative approach for TSC2-deficient tumors, possibly overcoming the limitations of current mTOR-inhibitor therapies, which often result in tumor regrowth upon cessation. Further research and clinical trials are warranted to explore the full potential of CHK1/2 inhibition in managing TSC-related tumors.
Lead author: Jeff MacKeigan, PhD, Professor of Pediatrics and Human Development and a senior advisor for Michigan State University Office of Research and Innovation, Michigan State University College of Human Medicine, Grand Rapids, Michigan.
Read the full paper here.
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