Reference Detail

Ref Type

Journal Article

PMID

(37014264)

Authors

Olson BM, Chaudagar K, Bao R, Saha SS, Hong C, Li M, Rameshbabu S, Chen R, Thomas A, Patnaik A

Title

BET Inhibition Sensitizes Immunologically Cold Rb-Deficient Prostate Cancer to Immune Checkpoint Blockade.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	22	6	2023 Jun 01	751-764	Mol Cancer Ther

URL

Abstract Text

Non-T-cell-inflamed immunologically "cold" tumor microenvironments (TME) are associated with poor responsiveness to immune checkpoint blockade (ICB) and can be sculpted by tumor cell genomics. Here, we evaluated how retinoblastoma (Rb) tumor-suppressor loss-of-function (LOF), one of the most frequent alterations in human cancer and associated with lineage plasticity, poor prognosis, and therapeutic outcomes, alters the TME, and whether therapeutic strategies targeting the molecular consequences of Rb loss enhance ICB efficacy. We performed bioinformatics analysis to elucidate the impact of endogenous Rb LOF on the immune TME in human primary and metastatic tumors. Next, we used isogenic murine models of Rb-deficient prostate cancer for in vitro and in vivo mechanistic studies to examine how Rb loss and bromodomain and extraterminal (BET) domain inhibition (BETi) reprograms the immune landscape, and evaluated in vivo therapeutic efficacy of BETi, singly and in combination with ICB and androgen deprivation therapy. Rb loss was enriched in non-T-cell-inflamed tumors, and Rb-deficient murine tumors demonstrated decreased immune infiltration in vivo. The BETi JQ1 increased immune infiltration into the TME through enhanced tumor cell STING/NF-κB activation and type I IFN signaling within tumor cells, resulting in differential macrophage and T-cell-mediated tumor growth inhibition and sensitization of Rb-deficient prostate cancer to ICB. BETi can reprogram the immunologically cold Rb-deficient TME via STING/NF-κB/IFN signaling to sensitize Rb-deficient prostate cancer to ICB. These data provide the mechanistic rationale to test combinations of BETi and ICB in clinical trials of Rb-deficient prostate cancer.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RB1 del	prostate cancer	sensitive	JQ1 + unspecified PD-L1 antibody	Preclinical	Actionable	In a preclinical study, the combination of JQ1 and an anti-PD-L1 therapy inhibited tumor growth in a syngeneic mouse model of RB1-deficient prostate cancer (PMID: 37014264).	37014264
RB1 del	prostate cancer	sensitive	JQ1	Preclinical	Actionable	In a preclinical study, JQ1 treatment inhibited tumor growth in a syngeneic mouse model of RB1-deficient prostate cancer (PMID: 37014264).	37014264