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. Author manuscript; available in PMC: 2024 Jun 1.
Published in final edited form as: Clin Cancer Res. 2023 Dec 1;29(23):4930–4940. doi: 10.1158/1078-0432.CCR-23-1441

Figure 4. PI3Ki/MEKi/PORCNi combination therapy suppresses lactate production from PTEN/p53-deficient GEM tumor-derived PC cells and secondary histone lactylation within activated TAM, resulting in enhanced TAM phagocytosis.

Figure 4.

(A) AC1/SC1 cells were treated with copanlisib (C, 100 nM), trametinib (T, 5 nM), LGK`974 (L, 50 nM) or their combination for 72 hours. For mechanistic dissection, lactate (lac, 100 nmol/μL) and LGK`974 (eL, 50nM) were added to the CM collected after C+T+L and C+T treatments of AC1/SC1 cells, respectively. FACS-sorted TAM were incubated with the indicated CM for 24 hours followed by co-culture with CTV dye stained-AC1/SC1 cells for 2 hours. (B) Bar graphs demonstrate fold change (FC) in histone lactylation and phagocytic activity of MHC-IIhi/PD-1hi/lo expressing TAM, relative to untreated group. n = 2 independent biological experiments. Significances/p-values were calculated by one-way ANOVA and indicated as follows, ***p<0.001.