Therapeutic Targeting of a Robust Non-Oncogene Addiction to PRKDC in ATM -Defective Tumors

Abstract

When the integrity of the genome is threatened, cells activate a complex, kinase-based signaling network to arrest the cell cycle, initiate DNA repair, or, if the extent of damage is beyond repair capacity, induce apoptotic cell death. The ATM protein lies at the heart of this signaling network, which is collectively referred to as the DNA damage response (DDR). ATM is involved in numerous DDR-regulated cellular responses-cell cycle arrest, DNA repair, and apoptosis. Disabling mutations in the gene encoding ATM occur frequently in various human tumors, including lung cancer and hematological malignancies. We report that ATM deficiency prevents apoptosis in human and murine cancer cells exposed to genotoxic chemotherapy. Using genetic and pharmacological approaches, we demonstrate in vitro and in vivo that ATM-defective cells display strong non-oncogene addiction to DNA-PKcs (DNA-dependent protein kinase catalytic subunit). Further, this dependence of ATM-defective cells on DNA-PKcs offers a window of opportunity for therapeutic intervention: We show that pharmacological or genetic abrogation of DNA-PKcs in ATM-defective cells leads to the accumulation of DNA double-strand breaks and the subsequent CtBP-interacting protein (CtIP)-dependent generation of large single-stranded DNA (ssDNA) repair intermediates. These ssDNA structures trigger proapoptotic signaling through the RPA/ATRIP/ATR/Chk1/p53/Puma axis, ultimately leading to the apoptotic demise of ATM-defective cells exposed to DNA-PKcs inhibitors. Finally, we demonstrate that DNA-PKcs inhibitors are effective as single agents against ATM-defective lymphomas in vivo. Together, our data implicate DNA-PKcs as a drug target for the treatment of ATM-defective malignancies.

Novel Aberrations Uncovered in Barrett's Esophagus and Esophageal Adenocarcinoma Using Whole Transcriptome Sequencing

“…However, PRKDCs is also a central regulator of transcriptional networks, facilitating tumor formation and progression (47). PRKDC may also have clinical relevance as a predictor of sensitivity to chemotherapy, as reported for esophageal SCC (48), and it has been reported as an attractive novel chemotherapeutic target (34).…”

“…S4B). Despite this, some of the genes identified as producing lowest cell viabilities if knocked down, such as PRKDC, may potentially be exploited as therapeutic targets (34).…”

The genetic classification of pancreatic neoplasia

“…Tumors harboring Fanconi anemia pathway gene mutations (such as BRCA1, BRCA2, and PALB2 mutations) and tumors harboring ATM mutations are examples of potential individualized treatment targets. It has been shown that this subgroup of PDAs is more amenable to DNA cross-linking drugs and to poly(ADP-ribose) polymerase inhibitors [54,[62][63][64][65][66]. In addition, PDAs with microsatellite instability, on the basis of experience with colorectal cancers with microsatellite instability, are less likely to be sensitive to 5-fluorouracil than are microsatellite-stable pancreatic cancers [67].…”

“…These include, for example, BRCA2, PALB2, ATM, BAP1, BRAF, and JAK1 mutations [11]. In particular, ACCs with an ATM mutation might be predicted to respond to poly(ADPribose) polymerase inhibitors and inhibitors of DNAdependent protein kinase catalytic subunit [63,64]. Novel strategies may also be use to try to treat RAF-gene-fusionpositive ACC with mitogen-activated protein/extracellularsignal-regulated kinase kinase inhibitors [145] as previously described in melanomas with BRAF fusions [146].…”

Adenocarcinoma of the Pancreas

“…24,25 PARP inhibitors, external beam radiation therapy and DNA-PKcs (protein kinase DNA-activated catalytic polypeptide) inhibitors may all be selectively effective in these patients. 41,42 The take-home message of all of this is that soon pathologists will be asked not only about cancer morphology, but also about the genetic background in which the cancer has arisen. As William Osler said, "the good physician treats the disease; the great physician treats the patient who has the disease."…”