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Rapamycin-resistant PARP1 overexpression is a potential therapeutic target in lymphangioleiomyomatosis (LAM).

[lymphangioleiomyomatosis]

Rationale: Lymphangioleiomyomatosis (LAM) is a female-predominant cystic lung disease that can lead to respiratory failure. LAM cells typically have inactivating TSC2 mutations and mTORC1 activation. Clinical response to the mTORC1 inhibitors has been limited, prompting a search for additional therapy for LAM. In this study, we investigate the impact of TSC2 on the expression of poly (ADP-ribose) polymerase-1 (PARP1) that initiates the DNA repair pathway and test the efficacy of PARP1 inhibitors in the survival of TSC2-deficient cells. Methods: We analyzed publicly available expression arrays of TSC2-deficient cells and validated the findings using real-time RT-PCR, immunoblotting, and immunohistochemistry. We examined the impact of rapamycin and Torin 1 on PARP1 expression. We also tested the effect of PARP1 inhibitors NU1025 and DPQ on the survival of TSC2-deficient cells. Results: We identified the upregulation of PARP1 in TSC2-deficient cells relative to TSC2-addback cells. The transcript levels of PARP1 in TSC2-deficient cells were not affected by rapamycin. PARP1 levels were increased in TSC2-deficient cells, xenograft tumors of rat-derived Tsc2-deficient cells, renal cystadenomas from Tsc2+/- mice, and human LAM nodules. RNA interference of mTOR failed to reduce PARP1 levels. Proliferation and survival of TSC2-deficient cells was reduced in response to PARP1 inhibitor treatment, more so than TSC2-addback cells. Conclusions: TSC2-deficient cells exhibit higher levels of PARP1 relative to TSC2-addback cells in an mTOR-insensitive manner. PARP1 inhibitors selectively suppress the growth and induce apoptosis of TSC2-deficient LAM patient-derived cells. Targeting PARP1 may be beneficial in the treatment of LAM and other neoplasms with mTORC1 activation.