Misrepair in Context: TGFβ regulation of DNA repair
- 1Radiation Oncology, University of California, San Francisco, United States
- 2Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, United States
- 3Shenzhen Graduate School, Peking University, China
- 4CRUK/MRC Oxford Institute for Radiation Oncology (MRC), United Kingdom
- 5University of California, San Francisco, United States
Repair of DNA damage protects genomic integrity, which is key to tissue functional integrity. In cancer, the type and fidelity of DNA damage response is the fundamental basis for clinical response to cytotoxic therapy. Here we consider the contribution of transforming growth factor-beta (TGFβ), a ubiquitous, pleotropic cytokine that is abundant in the tumor microenvironment, to therapeutic response. The action of TGFβ is best illustrated in head and neck squamous cell carcinoma (HNSCC). Survival of HNSCC patients with human papilloma virus (HPV) positive cancer is more than double compared to those with HPV-negative HNSCC. Notably, HPV infection profoundly impairs TGFβ signaling. HPV blockade of TGFβ signaling, or pharmaceutical TGFβ inhibition that phenocopies HPV infection, shifts cancer cells from error-free homologous-recombination DNA double-strand-break (DSB) repair to error-prone alternative end-joining (altEJ). Cells using altEJ are more sensitive to standard of care radiotherapy and cisplatin, and are sensitized to PARP inhibitors. Hence, HPV-positive HNSCC is an experiment of nature that provides a strong rationale for the use of TGFβ inhibitors for optimal therapeutic combinations that improve patient outcome.
Keywords: Cancer, Transforming growth factor-β, DNA Repair, Tumor microenviroment, Genomic integrity, Cytotoxic (or anti-neoplastic) chemotherapeutic agents, Radiation therapy (radiotherapy)
Received: 31 May 2019;
Accepted: 06 Aug 2019.
Copyright: © 2019 Barcellos-Hoff, Liu, Lopez, Humphrey and Murnane. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Dr. Mary Helen Barcellos-Hoff, University of California, San Francisco, Radiation Oncology, San Francisco, 10016, NY, United States, email@example.com