Targeting the DNA damage response in cancer therapy

Division Of Basic Sciences - Nci

Investigators

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Abstract

The DNA damage response (DDR) identifies DNA lesions and promotes genomic stability by activating signaling pathways to control cell fate. Genomic instability is a hallmark of cancer and components of the DDR are frequently altered in cancer to allow DNA damage tolerance. The genomic instability of cancers and identification of frequent driver mutations in the DDR, provide opportunities for targeted therapies and the use of synthetic lethal interactions. We found a key role for the TLK1 and TLK2 kinases that regulated histone exchange in genomic stability and replication stress avoidance and found that their loss sensitized cancer cells to DDR inhibitors. We developed conditional alleles, as well as CRISPR based systems, to modulate TLK1/2 levels in cancer and are determining its impact on tumor growth and immunotherapy responses in breast and prostate cancer models. We continue to work towards identifying clinically useful small molecule inhibitors for future therapeutic approaches. We demonstrated previously that the loss of TLK activity induced the Alternative Lengthening of Telomeres (ALT) pathway and we recently reported an optical screening method to identify ALT modulators. This robustly identified histone deposition machinery as playing a key role in this pathway and we are pursuing the characterization of novel ALT modulators that are therapeutically targetable in order to identify potential methods to preferentially kill ALT+ tumor cells. Finally, we carried out a series of CRISPR/Cas9 based screens in vitro and in vivo to identify new modulators of DDR targeting therapies and we continue to validate and characterize hits from these screens with a focus on genes that modulate innate immunity.