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The Global ETD Search service is a free service for researchers
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Showing 1 to 2 of 2 (0.079 seconds)Spelling suggestions: "subject:"oncogenic addiction""
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Unmasking Oncogene Addiction to the Epidermal Growth Factor Receptor in Triple Negative Breast Cancer: a Lesson in Intrinsic ResistanceCruz-Gordillo, Peter G. 24 August 2020 (has links)
The rationale behind targeted molecular therapy in cancer, oncogene addiction, is that tumors rely on driver oncogenes to control their proliferation and survival. Therefore, an efficacious targeted therapy should induce a dual, detrimental response to the tumor. While there have been clinical success stories using targeted therapies, even tumors that are initially sensitive invariably develop resistance. In the case of triple negative breast cancer (TNBC), despite extensive evidence pointing to its driver oncogene status, inhibitors of the Epidermal Growth Factor Receptor (EGFR) are considered clinically inefficacious. Resistance to EGFR inhibition has been predominantly described as due to genetic alterations. Yet it remains unclear why patients exhibiting the same dysregulated status of a driver oncogene react to targeted therapy, as in the case of EGFR-mutant non-small cell lung cancer, while others do not at all (i.e., TNBC). Furthermore, not all of resistance can be described by genetic alterations to EGFR, to its pathway effectors, or to compensatory pathways.
Emerging data reveals that drugs can induce resistance by rewiring epigenomic, transcriptional, and translational regulatory mechanisms. Unfortunately, a major limitation in designing efficacious treatments is our inability to predict whether cell types can rewire in response to drug exposure. Therefore, it is necessary to elucidate mechanisms of growth and survival in cells that have undergone rewiring. This study characterized intrinsic resistance to EGFR inhibition in TNBC. We found that EGFR inhibition induces rewiring, which results in a resistant growth state that bypasses the EGFR-MAPK pathway as a whole. Additionally, we found that a tRNA-modifying complex masks the oncogene addiction status of EGFR in TNBC by stabilizing the protein abundance of a pro-survival protein. Importantly, this happens solely in the context of EGFR inhibition. Taken together, this study highlights potential therapeutic strategies for TNBC and strategies that can be used to improve our understanding of targeted therapy resistance, especially intrinsic resistance.
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Reversing Cancer Cell Fate: Driving Therapeutic Differentiation of Hepatoblastoma to Functional Hepatocyte-Like CellsSmith, Jordan L. 20 March 2020 (has links)
Background & Aims: Despite advances in surgical care and chemotherapeutic regimens, the five-year survival rate for Stage IV Hepatoblastoma (HB), the predominant pediatric liver tumor, remains at 27%. YAP1 and β-Catenin co-activation occurs in 80% of children’s HB; however, a lack of conditional genetic models precludes exploration of tumor maintenance and therapeutic targets. Thus, the clinical need for a targeted therapy remains unmet. Given the predominance of YAP1 and β-catenin activation in children’s tumors, I sought to evaluate YAP1 as a therapeutic target in HB.
Approach & Results: Herein, I engineered the first conditional murine model of HB using hydrodynamic injection to deliver transposon plasmids encoding inducible YAP1S127A, constitutive β-CateninDelN90, and a luciferase reporter to murine liver. Tumor regression was evaluated using in vivo bioluminescent imaging, and tumor landscape characterized using RNA sequencing, ATAC sequencing and DNA foot-printing. Here I show that YAP1 withdrawal in mice mediates >90% tumor regression with survival for 230+ days. Mechanistically, YAP1 withdrawal promotes apoptosis in a subset of tumor cells and in remaining cells induces a cell fate switch driving therapeutic differentiation of HB tumors into Ki-67 negative “hbHep cells.” hbHep cells have hepatocyte-like morphology and partially restored mature hepatocyte gene expression. YAP1 withdrawal drives formation of hbHeps by modulating liver differentiation transcription factor (TF) occupancy. Indeed, tumor-derived hbHeps, consistent with their reprogrammed transcriptional landscape, regain partial hepatocyte function and can rescue liver damage in mice.
Conclusions: YAP1 withdrawal, without modulation of oncogenic β-Catenin, significantly regresses hepatoblastoma, providing the first in vivo data to support YAP1 as a therapeutic target for HB. Modulating YAP1 expression alone is sufficient to drive long-term regression in hepatoblastoma because it promotes cell death in a subset of tumor cells and modulates transcription factor occupancy to reverse the fate of residual tumor cells to mimic functional hepatocytes.
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