Project description:Accumulating evidence indicates that patient- derived organoids (PDOs) can predict drug responses in the clinic. Metastasis is the main cause of death in colorectal cancer patients, and the treatment of patients with liver metastasis remains poor. Tumor heterogeneity is the cause of treatment failure. In this study, we aim the investigate the consistency of drug sensitivity for the matched primary and metastatic tumor in patients with liver metastasis.
Project description:HCC827 cells were grown in gradually increasing concentrations of cetuximab beginning at 0.1 ug/ml. Drug concentrations were slowly increased until the resistant cells were able to proliferate in 100 ug/ml of cetuximab. Individual clones of cetuximab resistant (CR; CR1 to CR4) cells were isolated and confirmed to be drug resistant. Number of samples: 5. Parental HCC827 as a control. 4 Cetuximab resistant clones
Project description:Unraveling the underlying mechanisms of cetuximab resistance in head and neck squamous cell carcinoma (HNSCC) is of major importance as many tumors remain non-responsive or become resistant. Out microarray results suggest that resistant cells still exhibit RAS-MAPK pathway signaling contributing to drug resistance, as witnessed by low expression of DUSP 5 and DUSP6, negative regulators of ERK1/2, and increased expression of AURKB, a key regulator of mitosis. Therefore, interrupting the RAS-MAPK pathway by an ERK1/2 inhibitor (apigenin) or an AURKB inhibitor (barasertib) might be a new strategy for overcoming cetuximab resistance in HNSCC 4 head and neck squamous cell carcinoma (HNSCC) cell lines were treated with either 15 nM cetuximab or PBS during 13 hours. For each cell line, differential gene expression was assessed between cetuximab and PBS treatments.
Project description:HCC827 cells were grown in gradually increasing concentrations of cetuximab beginning at 0.1 ug/ml. Drug concentrations were slowly increased until the resistant cells were able to proliferate in 100 ug/ml of cetuximab. Individual clones of cetuximab resistant (CR; CR1 to CR4) cells were isolated and confirmed to be drug resistant.
Project description:We conducted chromatin immunoprecipitation for H3K27ac and BRD4, followed by sequencing (ChIP-seq) to investigate super-enhancer (SE) for drug-resistant using cetuximab-resistant cells and control cells. SE analysis revealed that several unique SE-associated genes in cetuximab-resistant cells were identified.
Project description:Cetuximab (Erbitux) is an antibody drug against EGFR and commonly used in late stage HNSCC and metastatic colorectal cancer. The oncogenic mutation of certain genes are known to drive Cetuximab resistance such as K-RAS or b-RAF mutation. The aberrant activation of signaling pathways in the presence of Cetuximab treatment to overcome cellular stress contribute to acquired resistance to Cetuximab as well. To better understand the mechanisms and molecular patterns of Cetuximab resistant cells, the Cetuximab resistant cells are trained for examining the gene expression profile. The gene expression array is used for identify the molecular signature governing the Cetuximab resitance.
Project description:WES on cetuximab treated, untreated and release samples of two metastatic colorectal xenografts.
First case: 3 cetuximab treated samples, 3 placebo and 3 release.
Second case: 2 cetuximab treated samples, 2 placebo and 3 release.
Paired fastq.
Project description:EGFR blockade by the monoclonal antibodies cetuximab or panitumumab causes objective tumor regressions in selected patients with metastatic colorectal cancer (mCRC). However, residual disease reservoirs almost invariably remain even after maximal response to therapy, leading to treatment failure and tumor relapse. Using mCRC patient-derived xenografts (PDXs), we observed that residual cancer cells surviving EGFR inhibition exhibited gene expression patterns reminiscent of a quiescent subpopulation of normal intestinal secretory precursors with Paneth-cell traits. These drug-tolerant cells had reduced expression of EGFR-activating ligands, consistent with lower EGFR dependence, and displayed higher HER2/HER3 pathway activity and persistent PI3K signaling. Mechanistically, cell fate reprogramming towards the Paneth cell-like phenotype was mediated by inactivation of YAP – a master regulator of intestinal epithelium recovery after injury – following cetuximab-induced neutralization of the MAPK cascade. Clinically, tumors from patients in whom cetuximab was not effective were enriched for markers of secretory commitment/Paneth-cell differentiation. In PDX therapeutic experiments, Pan-HER antibodies minimized residual disease burden and induced long-term tumor control after treatment discontinuation. We propose that tolerance to EGFR inhibition in CRC is typified by the adaptive disengagement of an in-built lineage program that jointly drives intestinal regenerative signaling and tumorigenesis. Further, our findings motivate therapeutic strategies to pre-emptively target residual disease before acquisition of irreversible resistance.