Chemotherapy-induced CDA expression renders resistant non-small cell lung cancer cells sensitive to 5'-deoxy-5-fluorocytidine (5'-DFCR).

Gao, Yanyun; Zens, Philipp; Su, Min; Gemperli, Camila Anna; Yang, Haitang; Deng, Haibin; Yang, Zhang; Xu, Duo; Hall, Sean R R; Berezowska, Sabina; Dorn, Patrick; Peng, Ren-Wang; Schmid, Ralph Alexander; Wang, Wenxiang; Marti, Thomas Michael (2021). Chemotherapy-induced CDA expression renders resistant non-small cell lung cancer cells sensitive to 5'-deoxy-5-fluorocytidine (5'-DFCR). Journal of experimental & clinical cancer research : CR, 40(1), pp. 1-22. 10.1186/s13046-021-01938-2

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BACKGROUND

Pemetrexed (MTA) plus cisplatin combination therapy is considered the standard of care for patients with advanced non-small-cell lung cancer (NSCLC). However, in advanced NSCLC, the 5-year survival rate is below 10%, mainly due to resistance to therapy. We have previously shown that the fraction of mesenchymal-like, chemotherapy-resistant paraclone cells increased after MTA and cisplatin combination therapy in the NSCLC cell line A549. Cytidine deaminase (CDA) and thymidine phosphorylase (TYMP) are key enzymes of the pyrimidine salvage pathway. 5'-deoxy-5-fluorocytidine (5'-DFCR) is a cytidine analogue (metabolite of capecitabine), which is converted by CDA and subsequently by TYMP into 5-fluorouracil, a chemotherapeutic agent frequently used to treat solid tumors. The aim of this study was to identify and exploit chemotherapy-induced metabolic adaptations to target resistant cancer cells.

METHODS

Cell viability and colony formation assays were used to quantify the efficacy of MTA and cisplatin treatment in combination with schedule-dependent addition of 5'-DFCR on growth and survival of A549 paraclone cells and NSCLC cell lines. CDA and TYMP protein expression were monitored by Western blot. Finally, flow cytometry was used to analyze the EMT phenotype, DNA damage response activation and cell cycle distribution over time after treatment. CDA expression was measured by immunohistochemistry in tumor tissues of patients before and after neoadjuvant chemotherapy.

RESULTS

We performed a small-scale screen of mitochondrial metabolism inhibitors, which revealed that 5'-DFCR selectively targets chemotherapy-resistant A549 paraclone cells characterized by high CDA and TYMP expression. In the cell line A549, CDA and TYMP expression was further increased by chemotherapy in a time-dependent manner, which was also observed in the KRAS-addicted NSCLC cell lines H358 and H411. The addition of 5'-DFCR on the second day after MTA and cisplatin combination therapy was the most efficient treatment to eradicate chemotherapy-resistant NSCLC cells. Moreover, recovery from treatment-induced DNA damage was delayed and accompanied by senescence induction and acquisition of a hybrid-EMT phenotype. In a subset of patient tumors, CDA expression was also increased after treatment with neoadjuvant chemotherapy.

CONCLUSIONS

Chemotherapy increases CDA and TYMP expression thereby rendering resistant lung cancer cells susceptible to subsequent 5'-DFCR treatment.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Thoracic Surgery
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Thoraxchirurgie
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Tumour Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Translational Research Unit

UniBE Contributor:

Gao, Yanyun; Zens, Philipp Immanuel; Yang, Haitang; Deng, Haibin; Xu, Duo; Hall, Sean; Berezowska, Sabina Anna; Dorn, Patrick; Peng, Ren-Wang; Schmid, Ralph and Marti, Thomas

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

1756-9966

Language:

English

Submitter:

Thomas Michael Marti

Date Deposited:

06 Jul 2021 16:36

Last Modified:

06 Jul 2021 16:36

Publisher DOI:

10.1186/s13046-021-01938-2

PubMed ID:

33874986

Uncontrolled Keywords:

5′-DFCR Chemotherapy resistant Cisplatin Cytidine deaminase (CDA) DNA damage Non-small cell lung cancer Pemetrexed Thymidine phosphorylase (TYMP)

BORIS DOI:

10.48350/157376

URI:

https://boris.unibe.ch/id/eprint/157376

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