Abstract
Platinum-based DNA-damaging chemotherapy is standard-of-care for most patients with lung cancer but outcomes remain poor. This has been attributed, in part, to the highly effective repair network known as the DNA-damage response (DDR). ATR kinase is a critical regulator of this pathway, and its inhibition has been shown to sensitize some cancer, but not normal, cells in vitro to DNA damaging agents. However, there are limited in vivo proof-of-concept data for ATR inhibition. To address this we profiled VX-970, the first clinical ATR inhibitor, in a series of in vitro and in vivo lung cancer models and compared it with an inhibitor of the downstream kinase Chk1. VX-970 markedly sensitized a large proportion of a lung cancer cell line and primary tumor panel in vitro to multiple DNA damaging drugs with clear differences to Chk1 inhibition observed. In vivo VX-970 blocked ATR activity in tumors and dramatically enhanced the efficacy of cisplatin across a panel of patient derived primary lung xenografts. The combination led to complete tumor growth inhibition in three cisplatin-insensitive models and durable tumor regression in a cisplatin-sensitive model. These data provide a strong rationale for the clinical evaluation of VX-970 in lung cancer patients.
Highlights
DNA damaging agents such as cisplatin, etoposide, gemcitabine and ionizing radiation (IR) remain the cornerstone of cancer treatment, yet for most patients they provide only modest benefit
Most notably VX-970 has >100-fold selectivity for ATR over the related phosphatidylinositol 3’ kinase-related kinases (PIKK) including ataxia telangiectasia mutated (ATM) and DNA-PK, both of which are involved in alternative DNA repair processes
To demonstrate the impact of VX-970 on cisplatininduced ATR signaling and DNA repair, H2009 lung cancer cells were treated with VX-970 and cisplatin as single agents or in combination (Figure 1B)
Summary
DNA damaging agents such as cisplatin, etoposide, gemcitabine and ionizing radiation (IR) remain the cornerstone of cancer treatment, yet for most patients they provide only modest benefit. A complex signaling pathway known as the DNA damage response (DDR) constitutes an important component of this network [5] It is activated by some of the most lethal forms of DNA damage including double strand breaks and replicative stress, which arises when DNA replication forks stall. ATR, on the other hand, is recruited to tracts of single stranded DNA coated with replication protein A (RPA), a characteristic of stalled replication forks (replication stress) and resected double strand breaks that arise during the S and G2 phases of the cell cycle. While these two kinases respond to different DNA damage structures, they exhibit significant functional and signaling overlap. Inhibition of ATR can lead to activation of ATM and a compensatory DDR[8]
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