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Selinexor reduces the expression of DNA damage repair proteins and sensitizes cancer cells to DNA damaging agents


2019-04-10

The goal of this study was to examine the effects of selinexor, an inhibitor of exportin-1 mediated nuclear export, on DNA damage repair and to evaluate the cytotoxic effects of selinexor in combination with DNA damaging agents in cancer cells. In contrast, enhanced cell death was not detected in cells that were pretreated with selinexor then with DDAs. The sequential combination of DDAs followed by selinexor increased cancer cell death.

Dr. Trinayan Kashyap from Karyopharm Therapeutics Inc., Newton, MA 02459, USA said "The export of large macromolecules from the nucleus to the cytoplasm is a highly dynamic and tightly regulated process."

In healthy cells, cell cycle arrest is needed to control normal tissue growth and to protect the integrity of cellular DNA from mutational assaults, such as free radicals from cellular metabolism, environmental toxins, or cancer treatments, including radiation and chemotherapy.

Once DNA damage is detected by a cellular surveillance mechanism, DNA damage response and cell cycle checkpoint proteins induce growth arrest and allow for repair. Nonredundant proteins execute the repair in a highly coordinated and complementary manner through five major repair pathways: direct reversal, nucleotide excision repair, base excision repair, mismatch repair, and recombination repair.

In this study, the research team demonstrated that selinexor significantly reduces the expression of DNA damage repair proteins, prevents recovery from DNA damage, and synergizes with DNA damage -inducing chemotherapies to stimulate cell death and reduce tumor size. In addition, the extent of repair protein repression by selinexor correlates with overall sensitivity of cancer cells to the drug.

The Trinayan Kashyap research team concluded, "the findings presented in this study suggest that the sequential treatment of DNA damage inducing chemotherapeutic agents followed by selinexor results in therapeutic synergy."

Full text - http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=25637&path%5B%5D=80235

Correspondence to - Trinayan Kashyap - tkashyap@karyopharm.com

Keywords - DNA damage repair, selinexor, nuclear export, chemotherapy



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