Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion

Abstract

Tuberous sclerosis complex (TSC) is characterized by tumor development in the brain, heart, kidney, and lungs. In TSC tumors, loss of the TSC1/TSC2 protein complex leads to activation of mTORC1 with downstream effects on anabolism and cell growth. Because mTORC1 activation enhances mRNA transcription, we hypothesized that aberrant mTORC1 activation might confer TSC-null cell dependence on transcriptional regulation. We demonstrate that TSC1- or TSC2-null cells, in contrast to their wild-type counterparts, are sensitive to pharmacological inhibition of CDK7. Mechanistic studies revealed that CDK7 inhibition markedly reduces glutathione levels and increases reactive oxygen species due to reduced expression of NRF2 and glutathione biosynthesis genes. Treatment of both Tsc2+/− mice and a TSC1-null bladder cancer xenograft model with a CDK7 inhibitor showed marked reduction in tumor volume and absence of regrowth in the xenograft model. These results suggest that CDK7 inhibition is a promising therapeutic approach for treatment of TSC-associated tumors and cancers with mutations in either TSC1 or TSC2.

The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis downstream of growth signals

“…The transcription factor NRF2 (also known as NFE2L2) is activated by oxidative stress and is a master regulator of the enzymes required for glutathione synthesis, as well as SLC7A11 to increase cystine uptake (Habib et al, 2015; Sasaki et al, 2002; Ye et al, 2014). While NRF2 depletion has been described to decrease the viability of cells with TSC gene loss (Zarei et al, 2019), we have no evidence from this or previous studies that mTORC1 signaling influences the levels or activity of NRF2 (Zhang et al, 2014).…”

The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis downstream of growth signals

“…The transcription factor NRF2 (also known as NFE2L2) is activated by oxidative stress and is a master regulator of the enzymes required for glutathione synthesis, as well as SLC7A11 to increase cystine uptake (Habib et al, 2015;Sasaki et al, 2002;Ye et al, 2014). While NRF2 depletion has been described to decrease the viability of cells with TSC gene loss (Zarei et al, 2019), we have no evidence from this or previous studies that mTORC1 signaling influences the levels or activity of NRF2 (Zhang et al, 2014). mTORC1 serves to couple growth signals to the coordinated control of anabolic processes, including the biosynthesis of protein, lipids, and nucleotides, as well as metabolic pathways that support this anabolic state (Valvezan & Manning, 2019).…”

Combination of chemotherapy and oxidative stress to enhance cancer cell apoptosis

“…4,34,61 Thus, targeting GSH inhibition has been considered as an effective way to kill cancer cells. 8,62 The release of the active drug Gem and conversion of the antioxidant GSH to ROS account for the enhanced cytotoxicity of Se-Gem. The accumulation of GSSG and ROS was also observed in the Hep G2 cells treated with Se-Gem.…”