( I) Representative micro-CT images of the lungs of LSL-Kras G12D/+ Trp53 fl/fl genetically engineered mice. ( H) Kaplan-Meier survival analysis of LSL-Kras(G12D) mice ( n = 6 per group). ( G) Representative images of H&E-stained unilateral lung lobe tissues after treatment.
( F) Representative lung micro-CT images of LSL-Kras(G12D) mice. Mice were treated according to the schedule in E. The mean AUC of tumor volumes (AUC TV) on day 21 is shown. ( E) Tumor volume (fold change) of patient-derived NSCLC (LACPDX) xenografts in mice ( n = 10 per group). P values were determined by unpaired, 2-tailed Student’s t test, comparing the combination treatment group with the control group. Data represent the mean ± SD of biological triplicates. ( C) Clonogenic assay of primary KRAS-mutant NSCLC cells. Scale bars: 0.1 cm (dark) and 1 cm (white). ( B) Representative images of 3D colony formation assays of A549 cells in response to the indicated treatments. CI values of less than 1 represent synergism. CI values at ED 50, ED 75, and ED 90 were calculated using CalcuSyn software. ( A) Synergistic interaction between BCL6 inhibitors (FX1 and Compound 7) and BETi (OTX015, JQ1, and I-BET762) in KRAS-mutant NSCLC cells. Overall, our findings identify a mechanism of BRD3-mediated BCL6 autoregulation and further develop an effective combinatorial strategy to circumvent BETi resistance in KRAS-driven NSCLC. Importantly, pharmacological inhibition of either BCL6 or mTOR improved the tumor response and enhanced the sensitivity of KRAS-mutant NSCLC to BETi in both in vitro and in vivo settings. Disrupting this negative autoregulation by BET inhibitors (BETi) resulted in a striking increase in BCL6 transcription, which further activated the mTOR signaling pathway through repression of the tumor suppressor death-associated protein kinase 2. We further found that BRD3, not BRD2 or BRD4, directly interacted with BCL6 and maintained the negative autoregulatory circuit of BCL6. Here, we demonstrate that BCL6 was upregulated upon BET inhibition in KRAS-mutant cancers, including non–small-cell lung cancer (NSCLC). Recently, the emerging role of the oncoprotein B cell lymphoma 6 (BCL6) in tumorigenesis and stress response has been unveiled. The bromodomain and extra-terminal domain (BET) proteins are promising therapeutic targets to treat refractory solid tumors however, inherent resistance remains a major challenge in the clinic.
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