Molecular Pathways: Exploiting Tumor-Specific Molecular Defects in DNA Repair Pathways for Precision Cancer Therapy

Abstract

Disabling mutations in genome maintenance and DNA repair pathways are frequently observed in cancer. These DNA repair defects represent genetic aberrations that are specific to cancer cells and not present in healthy tissues. It is thought that these molecular defects produce a "mutator phenotype," which allows incipient cancer cells to accumulate additional cancer-promoting mutations. In recent years, our molecular understanding of DNA double-strand break (DSB) repair mechanisms has led to the development of targeted therapeutic approaches to selectively eradicate cancer cells that display defects in homologous recombination-mediated DNA DSB repair. These regimens for the treatment of homologous recombination-defective tumors predominantly aim at pharmacologically repressing the activity of PARP1, which is crucial for base excision repair, or to inhibit the nonhomologous end joining kinase DNA-PKcs (DNA-dependent protein kinase, catalytic subunit). Normal tissue can bypass PARP1-or DNA-PKcs inhibitor-induced genotoxic lesions via homologous recombination-mediated DNA DSB repair. In contrast, homologous recombination-defective cancer cells are unable to properly repair DNA DSBs, in the presence of PARP1 or DNA-PKcs inhibitors, ultimately leading to apoptotic cancer cell death. Clin Cancer Res; 20(23); 5882-7. Ó2014 AACR.

Differential Proteomic Analysis between Small Cell Lung Carcinoma (SCLC) and Pulmonary Carcinoid Tumors Reveals Molecular Signatures for Malignancy in Lung Cancer

“…PRKDC, also known as DNA‐PKcs, plays a major role in DNA repair mechanisms with the non‐homologous end‐joining repair process, a repair pathway for double strand breaks. PRKDC levels are strongly upregulated and associated with a poor clinical outcome in various tumor types . Both SMC3 and RAD21 are components of the cohesin complex, which is required for chromosome cohesion during the cell cycle and is involved in DNA repair and apoptosis.…”

Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia

“…27 NHEJ is active throughout the cell cycle, whereas homologous recombination mediated by ATM/ATR is active in late S phase and in G 2 . [28][29][30] As peripheral blood CLL cells are in cell cycle arrest, 31 it is likely that DNA repair in CLL cells predominantly depends on NHEJ.…”

Targeted therapies in gynaecological cancers

“…It is this dependence of HRR‐deficient cells on alternative DNA repair mechanisms, and as a consequence PARP function, that renders them uniquely sensitive to treatment with PARP inhibitors. PARP inhibition produces stalled replication forks, increasing the number of dsDNA breaks, leading to genetic chaos and ultimately cell death …”