Abstract 4784
Background
Doxorubicin is an anthracycline antibiotic that acts as a DNA intercalating agent, inhibiting the topoisomerase II and inducing the apoptotic cell death, mainly due to the accumulation of double-strand DNA breaks (DSB). This research aims to identify in what way the abnormalities in microRNA (miRNA) expression profile in cancer cells can confer them the resistance to doxorubicin.
Methods
MiRNA targets within gene transcripts were predicted in silico using the TargetScan software.
Results
Binding sites for miRNAs miR-21, miR-96, miR-183 and miR-365, which are usually upregulated in cancer cells, were revealed in transcript of TOP2A gene encoding topoisomerase II-alpha. Transcripts of proapoptotic genes BID, BCL2L11 (BIM), BMF, BAX, BAK1, PMAIP1 (NOXA), and BBC3 (PUMA) as well as transcripts of tumor suppressor genes TP53 and PTEN carry targets for at least one of hyperexpressed miRNAs miR-19, miR-21, miR-23, miR-27, miR-29, miR-155, miR-181, miR-221/222 and miR-375. Downregulation of anti-onco-miRNAs let-7, miR-22, miR-34, miR-101, miR-125, miR-140, miR-143, miR-199, miR-200, miR-203, miR-204 and miR-205 allows overexpression of antiapoptotic genes BCL2, BCL2L1 (Bcl-XL), MCL1 and AKT1. In the same way, downregulation of the anti-onco-miRNAs can lead to overexpression of ABCA1/4/12, ABCB1 (MDR1), ABCB6, ABCC1 (MRP1) and ABCC3/5/8/11 genes encoding the ATP binding cassette (ABC) transporters. Moreover, multiple targets for the both up- and downregulated miRNAs were found in transcripts of XRCC5/6, PRKDC, LIG4, DCLRE1C, NHEJ1 (XLF), RAD50/51/51B/51D/52/54B/54L, MRE11A, NBN (NBS1), GEN1, ATM and ATR genes encoding the key elements of non-homologous end joining and homologous recombination pathways.
Conclusions
Obviously, in case of doxorubicin administration, strategy of early tumors consists in strengthening of miR-21 expression with the purpose to silence TOP2A gene and escape from immediate apoptotic death. Advanced tumors with more profound abnormalities in miRNA signature overexpress antiapoptotic genes as well as genes responsible for DSB repair and drug efflux and, therefore, can do without the TOP2A silencing.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Palladin Institute of Biochemistry of the National Academy of Sciences of Ukraine.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
3683 - Impact of Radiotherapy on efficacy of anti-programmed death 1 (PD-1) antibodies in metastatic NSCLC
Presenter: Evangeline Samuel
Session: Poster Display session 1
Resources:
Abstract
3924 - Pembrolizumab frontline monotherapy in patients with NSCLC and high PD-L1 expression: Real World Data from a European Cohort with focus on subgroups of interest
Presenter: Giannis Mountzios
Session: Poster Display session 1
Resources:
Abstract
3970 - Patients with metastatic non-small cell lung cancer and PD-L1 expression in Germany. Treatment and first outcome from the prospective German Registry Platform CRISP (AIO-TRK-0315)
Presenter: Martin Sebastian
Session: Poster Display session 1
Resources:
Abstract
5350 - The efficacy and safety of pembrolizumab as a first-line therapy in PD-L1 50% positive advanced NSCLC (HOPE-001)
Presenter: Motohiro Tamiya
Session: Poster Display session 1
Resources:
Abstract
3832 - Osimertinib in epidermal growth factor receptor (EGFR) T790M advanced non-small cell lung cancer (NSCLC): analysis of patients with central nervous system (CNS) metastases in a real-world study (ASTRIS)
Presenter: Giulio Metro
Session: Poster Display session 1
Resources:
Abstract
4082 - Real-world (RW) treatment patterns and outcomes for second-line (2L) therapy and beyond in patients (pts) with epidermal growth factor receptor-mutated (EGFRm) advanced NSCLC receiving a first-line (1L) first- or second-generation (1G/2G) EGFR tyrosine kinase inhibitor (TKI)
Presenter: Riyaz Shah
Session: Poster Display session 1
Resources:
Abstract
2855 - Impact of ramucirumab (RAM) + erlotinib (ERL) on EGFR mutations in circulating tumor DNA – The 1st report of a biomarker study in Japanese patients from RELAY: Global Ph3 study of ERL + RAM or placebo (PL) in 1L metastatic NSCLC with EGFR activating mutations
Presenter: Kazuto Nishio
Session: Poster Display session 1
Resources:
Abstract
2911 - Apatinib combined with EGFR - TKI in treating advanced non-small cell lung cancer with EGFR - TKI resistance
Presenter: Ruifen Tian
Session: Poster Display session 1
Resources:
Abstract
2100 - Updated analysis of a phase I trial of afatinib (Afa) and bevacizumab (Bev) in chemo-naïve patients (pts) with advanced non-small-cell lung cancer (NSCLC) harboring EGFR-mutations: OLCSG1404
Presenter: Takashi Ninomiya
Session: Poster Display session 1
Resources:
Abstract
4325 - Multiple synchronous mechanisms may contribute to osimertinib resistance in non-small cell lung cancer (NSCLC) patients: insights of the MATCH-R study
Presenter: Diego Enrico
Session: Poster Display session 1
Resources:
Abstract