Oncotarget

Research Papers:

Candidate drugs associated with sensitivity of cancer cell lines with DLST amplification or high mRNA levels

Christina Kuhn _, Myriam Boeschen, Manuel Philip, Torsten Schöneberg, Doreen Thor and Susanne Horn

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Abstract

Christina Kuhn1, Myriam Boeschen2, Manuel Philip3, Torsten Schöneberg1, Doreen Thor1,* and Susanne Horn1,3,*

1 Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, University of Leipzig, Leipzig 04103, Germany

2 Institute of Pathology, Medical Faculty, University of Leipzig, Leipzig 04103, Germany

3 Department of Dermatology, University Hospital Essen, University Duisburg-Essen, and German Cancer Consortium (DKTK) partner site Essen/Düsseldorf, Essen 45122, Germany

* These authors contributed equally to this work

Correspondence to:

Christina Kuhn, email: [email protected]

Keywords: neuroblastoma; drug sensitivity; drug resistance; drug repurposing; DLST

Received: July 12, 2022     Accepted: December 20, 2022     Published: January 12, 2023

Copyright: © 2023 Kuhn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

Overexpression of the dihydrolipoamide S-succinyltransferase (DLST) is associated with poor outcome in neuroblastoma patients and triple-negative breast cancer (TNBC) and specifically with the oxidative phosphorylation (OXPHOS) pathway. Inhibitors of OXPHOS were previously suggested as a potential therapeutic strategy for a subset of patients with high-risk neuroblastoma. Here, we tested if cell lines with DLST amplifications or high mRNA levels were associated with sensitivity to 250 drugs from the Genomics of Drug Sensitivity in Cancer (GDSC) dataset by comparing them to cell lines without these changes. DLST-altered cell lines were more sensitive to 7 approved drugs, among these obatoclax mesylate, a BCL2 inhibitor that reduces OXPHOS in human leukemia stem cells. Moreover, several protein kinase inhibitors were identified to be efficient in cell lines with DLST amplifications or high mRNA levels, suggesting a vulnerability of DLST-altered cell lines for drugs targeting the ERK/MAPK pathway. Furthermore, increased DLST expression in cell lines with driver mutations in KRAS supported this relationship. We therefore conclude that, in addition to OXPHOS, protein kinases could be potential targets of therapy in the presence of DLST amplifications or high mRNA levels. The new drug candidates proposed here could serve in experimental testing on drug efficacy in knock-in cell lines and DLST-activated tumors.


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