Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR

Abstract

Oncogenic Ras and p53 loss-of-function mutations are common in many advanced sporadic malignancies and together predict a limited responsiveness to conventional chemotherapy. Notably, studies in cultured cells have indicated that each of these genetic alterations creates a selective sensitivity to ataxia telangiectasia and Rad3-related (ATR) pathway inhibition. Here, we describe a genetic system to conditionally reduce ATR expression to 10% of normal levels in adult mice to compare the impact of this suppression on normal tissues and cancers in vivo. Hypomorphic suppression of ATR minimally affected normal bone marrow and intestinal homeostasis, indicating that this level of ATR expression was sufficient for highly proliferative adult tissues. In contrast, hypomorphic ATR reduction potently inhibited the growth of both p53-deficient fibrosarcomas expressing H-ras G12V and acute myeloid leukemias (AMLs) driven by MLL-ENL and N-ras G12D . Notably, DNA damage increased in a greater-than-additive fashion upon combining ATR suppression with oncogenic stress (H-ras G12V , K-ras G12D , or c-Myc overexpression), indicating that this cooperative genome-destabilizing interaction may contribute to tumor selectivity in vivo. This toxic interaction between ATR suppression and oncogenic stress occurred without regard to p53 status. These studies define a level of ATR pathway inhibition in which the growth of malignancies harboring oncogenic mutations can be suppressed with minimal impact on normal tissue homeostasis, highlighting ATR inhibition as a promising therapeutic strategy.

An extra allele of Chk1 limits oncogene-induced replicative stress and promotes transformation

“…In contrast, several studies have now shown that, over a threshold, the RS induced by Myc, Ras, or cyclin E oncogenes can be cytotoxic (Gilad et al, 2010;Murga et al, 2011;Toledo et al, 2011;Schoppy et al, 2012), which would rather argue that oncogeneinduced RS limits transformation. The data reported here favor the latter view, supporting that oncogeneinduced RS is a toxic byproduct of transformation, which is not needed by the oncogenes to trans form, and which decreases the fitness of transformed cells.…”

A Synthetic Lethal Screen Reveals Enhanced Sensitivity to ATR Inhibitor Treatment in Mantle Cell Lymphoma with ATM Loss-of-Function

“…These data suggest that ATR can use a complex, and coordinated set of proteins involved in intra-S checkpoint function to maintain genomic integrity. In this scenario, we hypothesize that these approaches may be expanded to other cancer types, in which high levels of replicative stress, like oncogene-induced, genomic instability or repair deficiencies may further expand the therapeutic window for treatment activity (12,34,41). …”

c-MYC-Induced Genomic Instability

“…Also, when MYC was inhibited through lentivirus-based shRNAs in human metastatic melanoma cell lines, the genes encoding enzymes important for dNTP metabolism were repressed and the amount of dNTPs were reduced (Mannava et al 2008). Last, Myc controls the ATR DNA repair pathway that is activated in response to specific single-stranded DNA produced during replication stress (Schoppy et al 2012). Components of this pathway are also potential therapeutic targets as their inhibition in cells with Myc overexpression can result in increased DNA damage and trigger an apoptotic response.…”