Combined inhibition of PARP and ATR synergistically potentiates the antitumor activity of HER2-targeting antibody-drug conjugate in HER2-positive cancers.

ABSTRACT: The therapeutic management of various HER2-positive malignancies involves the use of HER2-targeted antibody-drug conjugates (ADCs). The primary mechanism of action of ADCs is the release of cytotoxic chemicals, which leads to single- or double-strand DNA breaks and cell death. Since both endogenous and exogenous sources of DNA damage are unavoidable, cells have evolved DNA damage-repair mechanisms. Therefore, combining inhibitors of DNA damage repair and HER2-targeted ADCs may be a practical strategy for treating HER2-positive cancers. Effects of the HER2-targeted ADC, DS-8201, in combination with PARPi (AZD2281), a DNA damage repair inhibitor that targets poly(ADP-ribose) polymerase, and ATRi (BAY1895344), which inhibits the serine/threonine kinase ATR, were determined by assessing cell-g

SUBMITTER: Li Y 

PROVIDER: S-EPMC9906070 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature