Abstract IA13: CHK1 inhibitors: From concept to clinic

Abstract

Abstract Each cell in the human body is subjected daily to both exogenous and endogenous insults that result in DNA damage. This assault on the human genome can lead to the formation of many different types of DNA lesions such as single strand breaks (SSBs), double strand breaks (DSBs), base modifications and base mismatches that are repaired by a number of distinct but interrelated mechanisms. However, the failure to detect and repair these lesions can lead to cells with intrinsically high levels of DNA damage, gene mutations and often even larger genomic changes including chromosomal aberrations. These changes within the DNA may all contribute to the genome becoming unstable, such that there is an elevated frequency of genomic alterations. This genomic instability has now been acknowledged as a hallmark of cancer. Detection and response to DNA Damage is therefore essential for cells and is undertaken by the DNA damage response (DDR) pathway, an intracellular signaling network that coordinates and regulates the cellular activities that can detect and repair damaged DNA. A key component of this is pathway is the serine/threonine kinase CHK1. This kinase has the ability, through substrate phosphorylation to halt the cell division cycle, in particular at S and G2/M checkpoints. This gives the cell time to either repair the damaged DNA and re-initiate the cell cycle or if effective DNA repair is not possible, to induce cell senescence or cell death. The DDR is important for both normal and cancer cells. Cancer cells however, often have gene alterations that cause defects in one or more cell cycle checkpoints or in DNA repair. An important gene in this context is TP53 which encodes the p53 protein that can activate the G1/S cell cycle checkpoint in response to DNA damage. A hallmark of many tumors is the lack of functional p53 protein with a consequent loss of the G1/S checkpoint leading to a potential increased reliance on the S and G2/M checkpoints for survival. It was therefore initially hypothesized that CHK1 inhibitors may selectively enhance the activity of genotoxic agents in tumors, in particular by abrogating the G2 checkpoint, while normal cells would be rescued due to their competent DDR. This led to development a number of CHK1 inhibitors that are progressing towards, or are currently undergoing, clinical evaluation in combination with specific genotoxic cancer drugs. These include the potent, selective and orally bioavailable CHK1 inhibitor CCT245737, which is now scheduled for Phase I clinical trial and will be discussed during this presentation. Research now suggests that the role of CHK1 during S-phase may also be important when combining CHK1 inhibitors with selected chemotherapeutic agents and this will also be discussed. A key role for CHK1 during S phase is upon replication stress, where it stabilizes and preserves replication fork complexes thus preventing catastrophic replication fork collapse, until replication can be re-initiated. As well as suffering from genome instability, many cancer cells exhibit high levels of replication stress, which is thought to be due to oncogene-driven proliferation. Therefore tumors with high levels of replication stress will be dependent on functional CHK1. This provides a potential monotherapy strategy for CHK1 inhibitors in selected adult and pediatric cancer settings that are oncogene-driven and/or exhibit replication stress, which will be discussed in this presentation. Citation Format: Michelle D. Garrett. CHK1 inhibitors: From concept to clinic. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA13.