One of the hallmarks of cancer is genomic instability. A major source of genomic instability is a dysregulated cell cycle and aberrant DNA replication, resulting in a state of high replication stress (RS). High RS is manifested by stalled replication forks which expose fragile single stranded DNA that are prone to DNA damage. A major source of genomic instability in certain tumors arises as a consequence of dysregulated cell cycle checkpoints and aberrant DNA replication, resulting in high replication stress (RS), which is manifested by stalled replication forks and associated DNA damage.
Functional alterations in genes such as CCNE1, MYC, RAS, ATM, BRCA1, BRCA2, and TP53, which are prevalent in certain cancer cells, have been demonstrated to significantly increase RS. In such cancer cells, high levels of intrinsic RS result in near threshold levels of genomic instability.
Checkpoint kinase 1 (Chk1) is a serine-threonine kinase and master regulator of cell cycle progression and the DDR replication stress response. Chk1 regulates multiple cell-cycle phases, temporarily inhibiting the progression of cell replication and division in order to ensure proper replication of the genome and repair of collapsed or damaged replication forks. Chk1 stabilizes stalled replication forks, manages origin firing to avoid further replication stress, and mediates DNA repair via homologous recombination in the event of fork collapse.
Tumors with high RS become reliant on Chk1 to mitigate the potentially catastrophic consequences of excess genomic instability. As such, Chk1 represents a promising therapeutic target in cancers with high RS, as inhibiting Chk1 drives excessive genomic instability which can result in replication catastrophe and tumor cell death.
The standard chemotherapeutic drug gemcitabine profoundly depletes DNA replication building blocks, thereby functioning as a profound extrinsic inducer of replication stress, even at subtherapeutic concentrations. This provides a unique opportunity to potentially treat tumors harboring varying degrees of intrinsic replication stress with this novel combination.