Science

DNA Damage Response

DNA DAMAGE RESPONSE (DDR) NETWORK

DNA is continuously subject to damage due to a variety of endogenous and exogenous factors, against which cells have developed a complex system of mechanisms to resolve DNA damage and maintain genomic integrity, collectively known as the DNA Damage Response (DDR) network. Seminal discoveries related to the DDR network have been recognized in the award of the 2015 Nobel Prize in Chemistry and the 2015 Albert Lasker Basic Medical Research Award, and have contributed to the discovery of potential new treatments for cancer.

DNA is continuously subject to damage due to a variety of endogenous and exogenous factors.

Genomic instability – the accumulation of DNA damage and functional genomic alterations – is a key hallmark of cancer. The genomic instability of tumors provides them with a selective advantage over normal cells by enabling continual proliferation and survival, as well as by generating mechanisms for developing resistance to chemotherapy and other standards-of-care. Tumor cells accommodate genomic instability that results from mutation of certain cell cycle and DDR genes through an enhanced dependency on the remaining components of the DDR network to support their replication and viability.

An emerging therapeutic strategy to treat tumors is to target these vital components of the DDR network, such as Chk1 and Cdc7, either alone or in combination with DNA-damaging chemotherapeutics, in order to induce irreparable DNA damage, causing a catastrophic replicative process ultimately resulting in cell death. In contrast, non-transformed cells have multiple complementary DNA repair pathways, making them less sensitive to these agents. This strategy has been likened to striking at the ‘Achilles’ Heel’ of cancer, and therapeutic strategies increasingly are focusing on targeting the DDR network to exploit this intrinsic weakness of tumors.

Research into the DDR network has already contributed to the discovery of new treatments for cancer patients. Poly ADP-Ribose Polymerase inhibitors (PARPi) are the first approved DDR-targeting drugs. These agents demonstrate robust efficacy in patients with underlying defects in homologous recombination repair (HRR), an important DNA repair pathway within the DDR network.

Notwithstanding this success, the DDR network represents fertile ground for the development of new cancer therapies. While PARPi’s represent a major advance in the treatment of cancers with HRR deficiencies, other DDR targets with distinct biological functions are likely to provide broad benefit to patients whose tumors harbor distinct DDR network alterations. Among these emerging targets are Chk1 and Cdc7, where recent clinical and preclinical research suggest significant therapeutic potential through modulation of these proteins in hyperproliferating tumors with DDR alterations and genomic instability. Our DDR program is oriented to expanding beyond the scope of PARP inhibitors by striking at targets that control DNA replication, cell cycle progression and unique aspects of the DDR network.

The DDR network and the cell cycle.

The DNA Damage Response (DDR) network is a system of cellular pathways that monitor and repair DNA damage in an effort to maintain genomic integrity throughout the cell cycle.

The cell cycle comprises the sequence of coordinated events that take place in a cell, known as cell cycle phases, that enable the cell to faithfully duplicate its genomic DNA and divide into two daughter cells. The four phases are referred to as G1, S, G2 and M, and systematically regulate the growth, duplication and division of the cell.

Several proteins within the DDR network govern key transitions between the phases of the cell cycle and are collectively known as cell cycle checkpoints components. The DDR network can activate these cell cycle checkpoints to temporarily pause cellular replication in order to facilitate the repair of damaged DNA.

Cancer cells are over-reliant on the DDR network

Malignant cells can tolerate substantially greater levels of DNA damage and genomic instability compared to healthy cells. Certain standard chemotherapeutic agents and radiotherapy induce DNA damage in order to kill cancer cells, yet often cancer cells survive and persist despite this damage. Intrinsic replication stress induced by factors such as oncogenes (e.g., MYC or CCNE1), genetic mutations in DNA repair machinery (e.g., BRCA1 or BRCA2) combined with loss of function in tumor suppressors (e.g., TP53 or RAD50) results in persistent DNA damage and genomic instability leading to an increased dependency on the DDR network for survival.

Cancer cells can survive and replicate despite high levels of genomic instability and DNA damage due to an over-reliance on the remaining components of the DDR network that govern cell cycle checkpoints, such as Chk1 and Cdc7. By activating these cell cycle checkpoints, cancer cells can temporarily pause cellular replication in order to facilitate the repair of damaged DNA.

Importantly, many cancer cells intrinsically lack the G1/S cell cycle checkpoint, rendering these cells exquisitely dependent on the S or G2/M cell cycle checkpoints as mechanisms to temporarily pause the cell cycle in order to repair their damaged DNA. This is in contrast to healthy cells, which are less sensitive to specific checkpoint inhibition, as they retain their full complement of functional cell cycle checkpoints.

Cancer cells tolerate genomic instability and elevated DNA damage via an over-reliance on checkpoint components such as Chk1 and Cdc7.

Targeting the DDR network to treat cancer

In cancer cells lacking the G1/S checkpoint, targeted inhibition of the remaining components of the DDR network may be synthetically lethal to cancer cells compared to normal cells, and therefore of potential benefit in the treatment of certain cancers. Specifically, by inhibiting critical S or G2/M cell cycle and DNA replication checkpoint components, such as Chk1 and Cdc7, cancer cells may be rendered unable to repair their damaged DNA, and subsequently driven into a catastrophic replicative process ultimately resulting in cell death.

Many standard chemotherapeutics also induce DNA damage and may be synergistic with Chk1 and Cdc7 inhibitors.

SRA737 and SRA141 inhibit important targets with critical cell cycle checkpoint and DDR regulatory functions.