| dc.contributor.advisor | Dobbelstein, Matthias Prof. Dr. | |
| dc.contributor.author | Ewers, Katharina | |
| dc.date.accessioned | 2021-11-16T15:45:09Z | |
| dc.date.available | 2022-10-11T00:50:13Z | |
| dc.date.issued | 2021-11-16 | |
| dc.identifier.uri | http://hdl.handle.net/21.11130/00-1735-0000-0008-5989-A | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-8945 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 610 | |
| dc.title | Overcoming Cisplatin Resistance in Pancreatic Cancer | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Dobbelstein, Matthias Prof. Dr. | |
| dc.date.examination | 2021-10-12 | |
| dc.description.abstracteng | Pancreatic ductal adenocarcinoma (PDAC) is the most common species of pancreatic cancer with high lethality. Despite intensive research, no major therapy improvements have been achieved due to late-stage diagnosis and aggressive tumour biology resulting in low therapy response and poor survival of patients. Thus, PDAC is predicted to be the second leading cause of cancer-related death within the next decade. We were thus aiming at new treatment strategies.
We analysed the response of a panel of seven PDAC cell lines against the chemotherapeutic agent cisplatin, determining two clearly separated response categories, cisplatin-sensitive and resistant cells. Interestingly, the sensitive cells correspond to the classical form of molecular PDAC subtypes, displaying a less aggressive biology and relatively good prognosis for the patients. The cisplatin-resistant cells can be linked to the basal-like subtype, which is characterised by even higher aggressiveness, lower survival rate and chemo-resistance. Interestingly, the basal-like cells had a lower degree of platinised DNA upon treatment, which was reversed by an inhibitor of platinum export from cells. This suggests a higher degree of platinum export in basal-like cells as a mechanism of their resistance. Besides the transcription factor GATA6, which was already identified as a marker for the classical subtype, we could show that the expression of the microRNAs 200a and 200b could be linked to cisplatin-sensitive cells, serving as potential biomarkers for cisplatin responsiveness.
Previous results suggested that a combination of HSP90 inhibitors and the cisplatin analogue carboplatin resulted in a strong antitumour synergy in ovarian cancer cells. Here we found that in basal-like PDAC cells, the combination of HSP90 inhibition and cisplatin treatment resulted in a synergistic reduction of cell viability, increased DNA damage and chromosome fragmentation. These effects are mediated by the degradation of the DNA repair pathway protein FANCA. Further, cisplatin efflux by export transporter seemed compromised upon HSP90 inhibition, as the platinum-DNA adduct formation was increased upon HSP90 inhibition.
Moving towards clinical application, we transferred our approach into a mouse model with orthotopically transplanted KPC cells (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre; C57/BL6 genetic background). The combination treatment was highly efficient and resulted in a strong reduction of tumour size with increased apoptosis.
Our study suggests that PDAC cells show a distinct response towards cisplatin treatment and that combination of cisplatin with the HSP90 inhibitor onalespib is able to overcome cisplatin resistance in basal-like PDAC cells. | de |
| dc.contributor.coReferee | Heßmann, Elisabeth Pd Dr. | |
| dc.contributor.thirdReferee | Hahn, Heidi Prof. Dr. | |
| dc.subject.eng | Cancer | de |
| dc.subject.eng | Cisplatin | de |
| dc.subject.eng | Pancreatic Ductal Adenocarcinoma | de |
| dc.subject.eng | HSP90 inhibition | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-21.11130/00-1735-0000-0008-5989-A-4 | |
| dc.affiliation.institute | Medizinische Fakultät | |
| dc.subject.gokfull | Molekularbiologie {Medizin} (PPN619875186) | de |
| dc.description.embargoed | 2022-10-11 | |
| dc.identifier.ppn | 1777581508 | |