BH3 mimetics targeting BCL-XL have efficacy in solid tumors with RB1 loss and replication stress

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• BH3 mimetics targeting BCL-2, BCL-XL, or MCL-1 have shown limited effectiveness in solid tumors.
• Identifying specific tumor vulnerabilities and combination strategies is crucial for improving cancer treatment outcomes.

Purpose of the Study:

• To investigate the sensitivity of solid tumors to BCL-XL inhibition, particularly in the context of RB1 loss and replication stress.
• To explore the mechanistic basis for BCL-XL inhibitor sensitivity.
• To evaluate the therapeutic potential of combining BCL-XL inhibitors with agents that induce replication stress.

Main Methods:

• Assessment of xenograft-derived 3D prostate cancer models and cell lines.
• Drug screening to identify agents that sensitize tumors to BCL-XL inhibition.
• Mechanistic studies involving TP53/CDKN1A signaling and BIRC5 expression.
• In vivo therapy studies using BCL-2/BCL-XL inhibitors and thymidylate synthase inhibitors in prostate and breast cancer xenografts.

Main Results:

• Tumors with RB1 loss exhibit sensitivity to BCL-XL inhibition.
• Disruption of nucleotide pools via thymidylate synthase inhibitors sensitizes tumors to BCL-XL inhibition, indicating increased dependence on BCL-XL under replication stress.
• Replication stress sensitizes cells to BCL-XL inhibition through TP53/CDKN1A-dependent suppression of BIRC5.
• Combination therapy with navitoclax and thymidylate synthase inhibitors (raltitrexed or capecitabine) resulted in significant and durable tumor regression in xenograft models.

Conclusions:

• BCL-XL inhibitors may be effective as monotherapy in solid tumors with RB1 loss.
• Pharmacological induction of replication stress is a promising strategy to sensitize a broader range of solid tumors to BCL-XL inhibitors.
• These findings support the development of novel combination therapies for prostate and breast cancers.