Suppression of tumor cell lactate-generating signaling pathways eradicates murine PTEN/p53-deficient aggressive-variant prostate cancer via macrophage phagocytosis.

TitleSuppression of tumor cell lactate-generating signaling pathways eradicates murine PTEN/p53-deficient aggressive-variant prostate cancer via macrophage phagocytosis.
Publication TypeJournal Article
Year of Publication2023
AuthorsChaudagar K, Hieromnimon HM, Kelley A, Labadie B, Shafran J, Rameshbabu S, Drovetsky C, Bynoe K, Solanki A, Markiewicz E, Fan X, Loda M, Patnaik A
Date Published2023 May 23

PURPOSE: PTEN loss-of-function/PI3K pathway hyperactivation occurs in ∼50% of metastatic, castrate-resistant prostate cancer patients, resulting in poor therapeutic outcomes and resistance to immune checkpoint inhibitors across multiple malignancies. Our prior studies in prostate-specific PTEN/p53-deleted genetically engineered mice (Pb-Cre;PTEN fl/fl Trp53 fl/fl GEM) with aggressive-variant prostate cancer (AVPC) demonstrated feedback Wnt/β-catenin signaling activation in 40% mice resistant to androgen deprivation therapy (ADT)/PI3K inhibitor (PI3Ki)/PD-1 antibody (aPD-1) combination, resulting in restoration of lactate cross-talk between tumor-cells and tumor-associated macrophages (TAM), histone lactylation (H3K18lac) and phagocytic suppression within TAM. Here, we targeted immunometabolic mechanism(s) of resistance to ADT/PI3Ki/aPD-1 combination, with the goal of durable tumor control in PTEN/p53-deficient PC.

EXPERIMENTAL DESIGN: Pb-Cre;PTEN fl/fl Trp53 fl/fl GEM were treated with either ADT (degarelix), PI3Ki (copanlisib), aPD-1, MEK inhibitor (trametinib) or Porcupine inhibitor (LGK 974) as single agents or their combinations. MRI was used to monitor tumor kinetics and immune/proteomic profiling/ ex vivo co-culture mechanistic studies were performed on prostate tumors or established GEM-derived cell lines.

RESULTS: We tested whether Wnt/β-catenin pathway inhibition with LGK 974 addition to degarelix/copanlisib/aPD-1 therapy enhances tumor control in GEM, and observed de novo resistance due to feedback activation of MEK signaling. Based on our observation that degarelix/aPD-1 treatment resulted in partial inhibition of MEK signaling, we substituted trametinib for degarelix/aPD-1 treatment, and observed a durable tumor growth control of PI3Ki/MEKi/PORCNi in 100% mice via H3K18lac suppression and complete TAM activation within TME.

CONCLUSIONS: Abrogation of lactate-mediated cross-talk between cancer cells and TAM results in durable ADT-independent tumor control in PTEN/p53-deficient AVPC, and warrants further investigation in clinical trials.

STATEMENT OF TRANSLATIONAL RELEVANCE: PTEN loss-of-function occurs in ∼50% of mCRPC patients, and associated with poor prognosis, and immune checkpoint inhibitor resistance across multiple malignancies. Our prior studies have demonstrated that ADT/PI3Ki/PD-1 triplet combination therapy controls PTEN/p53-deficient PC in 60% of mice via enhancement of TAM phagocytosis. Here, we discovered that resistance to ADT/PI3K/PD-1 therapy occurred via restoration of lactate production via feedback Wnt/MEK signaling following treatment with PI3Ki, resulting in inhibition of TAM phagocytosis. Critically, co-targeting of PI3K/MEK/Wnt signaling pathways using an intermittent dosing schedule of corresponding targeted agents resulted in complete tumor control and significantly prolonged survival without significant long-term toxicity. Collectively, our findings provide "proof-of-concept" that targeting lactate as a macrophage phagocytic checkpoint controls growth of murine PTEN/p53-deficient PC and warrant further investigation in AVPC clinical trials.

Alternate JournalbioRxiv
PubMed ID37292972
PubMed Central IDPMC10245812
Grant ListP30 CA014599 / CA / NCI NIH HHS / United States
P50 CA180995 / CA / NCI NIH HHS / United States
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