Project description:Background: Cholesterol pathway inhibition by statins prevents breast cancer development in mouse models of breast cancer but their efficacy is not very high (about 50%) . Therefore, the goal of this study is to investigate if the fluvastatin mediated upregulation in the steroid biosynthesis pathway genes limit the efficacy of statin chemoprevention. Methods: A published gene signature of statin resistance was validated in cell line-based models of inherent and acquired resistance during breast cancer. These signatures were next validated in a mouse model of hormone receptor negative breast cancer. Results: We found more than 70% of a published multi-gene fluvastatin resistance signature to be significantly upregulated in an inherently resistant cell line relative to fluvastatin sensitive cell line. We found this inherent statin resistance gene signature to be also shared with the signature of acquired resistance to fluvastatin (13 / 23 total genes). These 13 inherent resistance genes and 10 additional genes mapped to 2 of the top 3 deregulated pathways that are steroid-, and terpenoid backbone- biosynthesis pathway. Next, we tested if one or multiple genes of statin resistance signature, could predict efficacy of statin chemoprevention in the SV40 C3TAg transgenic mouse model. We found upregulation of a large number (19/24) of genes in the tumor bearing mammary glands, suggesting that upregulation of these pathways drives resistance to statin chemoprevention. A subset of 13-genes from this panel was significantly associated with response to statin treatment, as was the expression level of HMGCR alone in a mouse model of breast cancer. Lastly, we studied if a 10-day period of fluvastatin treatment to SV40C3 TAg mice, can also trigger the upregulation of these genes and provide an early signal of statin resistance. These experiments showed that a 10-day period is insufficient to cause a feedback upregulation in steroid biosynthesis pathway genes and thus cannot be used as an early biomarker to detect resistance to fluvastatin. Conclusions: High basal or restorative upregulation in the steroid biosynthesis pathway gene expression after fluvastatin treatment appears to be strongly associated with resistance to statin chemoprevention for breast cancer and may serve as a biomarker to identify patients that are most likely to respond to statins or develop resistance.
Project description:Although immunotherapy with PD-(L)1 blockade is routine for lung cancer, little is known about acquired resistance. Among 1,201 patients with non-small cell lung cancer (NSCLC) treated with PD-(L)1 blockade, acquired resistance is common, occurring in >60% of initial responders. Acquired resistance shows differential expression of inflammation and interferon (IFN) signaling. Relapsed tumors can be separated by upregulated or stable expression of IFNγ response genes. Upregulation of IFNγ response genes is associated with putative routes of resistance characterized by signatures of persistent IFN signaling, immune dysfunction, and mutations in antigen presentation genes which can be recapitulated in multiple murine models of acquired resistance to PD-(L)1 blockade after in vitro IFNγ treatment. Acquired resistance to PD-(L)1 blockade in NSCLC is associated with an ongoing, but altered IFN response. The persistently inflamed, rather than excluded or deserted, tumor microenvironment of acquired resistance informs therapeutic strategies to effectively reprogram and reverse acquired resistance.
Project description:This study was conducted to identify dysregulated genes associated with acquired resistance to chemotherapy. Endoscopic biopsy samples were collected from CF-treated metastatic gastric cancer patients prior to therapy and following the development of resistance to therapy.
Project description:Despite the established use of immune checkpoint inhibitors to treat non-small cell lung cancer (NSCLC), only a subset of patients benefit from treatment and approximately 50% of patients whose tumors respond eventually develop acquired resistance. To identify novel drivers of acquired resistance, we generated murine Msh2 knock-out (KO) lung tumors that initially responded but eventually developed acquired resistance to anti-PD-1, alone or in combination with anti-CTLA-4. Resistant tumors harbored decreased infiltrating T cells and reduced cancer cell-intrinsic MHC-I and MHC-II levels, yet remained responsive to IFNɣ. Resistant tumors contained extensive regions of hypoxia, and a hypoxia signature derived from single-cell transcriptional profiling of resistant cancer cells was associated with decreased progression-free survival in a cohort of NSCLC patients treated with anti-PD-1/PD-L1 therapy. Targeting hypoxic tumor regions using a hypoxia activated pro-drug delayed acquired resistance to immune checkpoint inhibitors in murine Msh2 KO tumors. Thus, this work provides rationale for targeting tumor metabolic features, such as hypoxia, in combination with immune checkpoint inhibition.
Project description:Although immunotherapy with PD-(L)1 blockade is routine for lung cancer, little is known about acquired resistance. Among 1,201 patients with non-small cell lung cancer (NSCLC) treated with PD-(L)1 blockade, acquired resistance is common, occurring in >60% of initial responders. Acquired resistance shows differential expression of inflammation and interferon (IFN) signaling. Relapsed tumors can be separated by upregulated or stable expression of IFNγ response genes. Upregulation of IFNγ response genes is associated with putative routes of resistance characterized by signatures of persistent IFN signaling, immune dysfunction, and mutations in antigen presentation genes which can be recapitulated in multiple murine models of acquired resistance to PD-(L)1 blockade after in vitro IFNγ treatment. Acquired resistance to PD-(L)1 blockade in NSCLC is associated with an ongoing, but altered IFN response. The persistently inflamed, rather than excluded or deserted, tumor microenvironment of acquired resistance informs therapeutic strategies to effectively reprogram and reverse acquired resistance.
Project description:To investigate progestin resistance in endometrial cancer ,we examined the changes in gene expression before and after development of acquired MPA resistance. Results provide insight into molecular mechanisms of acquired resistance to MPA in endometrial cancer.
Project description:The goal of this study was to compare the transcriptome (RNA-seq) of EGFR TKI sensitive NSCLC cells with that of cells with acquired resistance to erlotinib. HCC827 and HCC4006 cells were continuously cultured in erlotinib until erlotinib resistant (ER) variants emerged. All ER variants were negative for T790M. RNA from parental and ER cells was isolated for transcriptomic profiling. RNA-seq analysis reveals that EGFR TKI resistance is associated with a mesenchymal gene expression signature.