PhD Scientific Days 2025

Poster Session III. - C: Molecular Medicine

Effect of a Combination of Selective CDK12 and PARP Inhibitors on PARP Inhibitor Resistant Breast Cancer Cell Lines

Előadó neve

Dr. Makkos András

Neptun code

olwgb8

Előadó munkahelye

Department of Pharmacology and Pharmacotherapy

Előadó telefonszáma

+3603707325

Előadó e-mail címe

makkos.andras@semmelweis.hu

Az előadás címe

Effect of a Combination of Selective CDK12 and PARP Inhibitors on PARP Inhibitor Resistant Breast Cancer Cell Lines

Szerző(k) neve és munkahelye

András Makkos¹, Orsolya Somogyi¹, Ákos Takács², Róbert Dóczi², István Peták², Anikó Görbe¹

1: Department of Pharmacology and Pharmacotherapy
2: Genomate Health Ltd.

Bemutatás módja

Poszter

Szekció

Poster Session III. - C: Molecular Medicine

Language of the presentation

English

Preferred session

Molecular Medicine

Összefoglaló szövege

DNA instability plays an important role in tumorigenesis. PARPs and BRCA1/2 genes play a key role in the mechanism of DNA error repair via homologous recombination. Mutations in the BRCA1/2 gene or inhibition of the PARP enzyme increase genetic instability. The combination of these two processes can lead to cell death, which is of therapeutic importance. The most common obstacle to this therapeutic effect is resistance to PARP inhibitors, which may be due to increased expression of cyclin-dependent kinase 12 (CDK12).

In the present study, we aimed to investigate the effect of selective CDK12 inhibition on CDK12-overexpressing and PARP inhibitor-resistant breast tumor cells.
Two breast tumor cell lines carrying BRCA1/2 mutations were examined to determine the copy number and protein expression of the CDK12 gene by gene sequencing and western blot methods. The effects of PARP inhibitor treatment and CDK12 inhibitor treatment were determined in the cell lines, individually and in combination. Cell survival at the end of the treatment protocol was determined by luminescence food viability measurements and compared using calculated IC50 values.
DNA sequencing in the MDA-MB-436 cell line revealed normal (n=2) CDK12 gene copy numbers, while BT-474 cells showed elevated (n=27) copy numbers. Similarly, Western blot CDK12 overexpression was observed in BT-474 (MDA-MB-436: 1.00±0.13 a.u. vs BT-474: 1.71±0.08* a.u.; t-test; *p<0.05).
The PARP inhibitor rucaparib was effective in reducing the viability of MDA-MB-436 cells (IC50: 52.04 μM), whereas the BT-474 cell line was resistant (IC50: 210.00 μM). Selective CDK12 inhibition was also more effective in MDA-MB-436 cells (IC50: 0.01 μM vs IC50: 0.10 μM). No synergism was observed when the two treatments were administered together.
Our results suggest that higher copy number and protein level of the CDK12 gene can be associated with both PAPR inhibitor resistance and increased sensitivity to CDK12 inhibitor. However, the tumor growth inhibitory effect of the two inhibitors does not show synergism in the cell types studied so far.

University

Semmelweis University

Supervisor

Anikó Görbe

Publication of my abstract

I do not give consent to the publication of my abstract on the website of the congress.

phd.section.field

after finishing doctoral studies with absolutorium (PhD)

Kind

Szabad

Status

elfogadva

Accepted presentation method

poszter

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

1293

Start

14:48

End

14:54