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Differential Activity of ATR and WEE1 Inhibitors in a Highly Sensitive Subpopulation of DLBCL Linked to Replication
Lucy A Young1, Lenka Oplustil O'Connor1, Christelle de Renty1
1Bioscience, Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
Abstract:
DNA damage checkpoint kinases ATR and WEE1 are among key regulators of DNA damage response pathways protecting cells from replication stress, a hallmark of cancer that has potential to be exploited for therapeutic use. ATR and WEE1 inhibitors are in early clinical trials and success will require greater understanding of both their mechanism of action and biomarkers for patient selection. Here, we report selective antitumor activity of ATR and WEE1 inhibitors in a subset of non-germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL) cell lines, characterized by high MYC protein expression and CDKN2A/B deletion. Activity correlated with the induction of replication stress, indicated by increased origin firing and retardation of replication fork progression. However, ATR and WEE1 inhibitors caused different amounts of DNA damage and cell death in distinct phases of the cell cycle, underlying the increased potency observed with WEE1 inhibition. ATR inhibition caused DNA damage to manifest as 53BP1 nuclear bodies in daughter G1 cells leading to G1 arrest, whereas WEE1 inhibition caused DNA damage and arrest in S phase, leading to earlier onset apoptosis. In vivo xenograft DLBCL models confirmed differences in single-agent antitumor activity, but also showed potential for effective ATR inhibitor combinations. Importantly, insights into the different inhibitor mechanisms may guide differentiated clinical development strategies aimed at exploiting specific vulnerabilities of tumor cells while maximizing therapeutic index. Our data therefore highlight clinical development opportunities for both ATR and WEE1 inhibitors in non-GCB DLBCL subtypes that represent an area of unmet clinical need. SIGNIFICANCE: ATR and WEE1 inhibitors demonstrate effective antitumor activity in preclinical models of DLBCL associated with replication stress, but new mechanistic insights and biomarkers of response support a differentiated clinical development strategy.
Insights
ATR and WEE1 inhibitors show promise against specific diffuse large B-cell lymphomas (DLBCL) by inducing replication stress. Understanding their distinct mechanisms and cell cycle effects is key for developing targeted cancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- DNA damage response pathways, regulated by ATR and WEE1 kinases, are crucial for protecting cells from replication stress, a common feature in cancer.
- ATR and WEE1 inhibitors are under clinical investigation, necessitating a deeper understanding of their mechanisms and patient selection biomarkers.
- Replication stress is a potential therapeutic target in cancer, particularly in subtypes like non-germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL).
Purpose of the Study:
- To investigate the selective antitumor activity of ATR and WEE1 inhibitors in DLBCL cell lines.
- To elucidate the distinct mechanisms of action and cell cycle effects of ATR and WEE1 inhibition in DLBCL.
- To identify potential biomarkers and guide differentiated clinical development strategies for ATR and WEE1 inhibitors in DLBCL.
Main Methods:
- Treatment of non-GCB DLBCL cell lines with ATR and WEE1 inhibitors.
- Assessment of replication stress markers, including origin firing and replication fork progression.
- Analysis of DNA damage, cell cycle arrest, apoptosis, and *in vivo* xenograft models.
Main Results:
- Selective antitumor activity of ATR and WEE1 inhibitors was observed in a subset of non-GCB DLBCL cell lines with high MYC expression and CDKN2A/B deletion.
- Inhibitor activity correlated with induced replication stress, evidenced by increased origin firing and slowed replication fork progression.
- ATR inhibition led to G1 arrest via 53BP1 nuclear bodies in daughter cells, while WEE1 inhibition caused S-phase arrest and earlier apoptosis.
Conclusions:
- ATR and WEE1 inhibitors exhibit distinct mechanisms and cell cycle effects, with WEE1 inhibition showing increased potency.
- *In vivo* models confirmed differential antitumor activity and highlighted potential for ATR inhibitor combinations.
- These findings support differentiated clinical development strategies for ATR and WEE1 inhibitors in non-GCB DLBCL, addressing an unmet clinical need.
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