The Selective WEE1 Inhibitor Azenosertib Shows Synergistic Antitumor Activity with KRASG12C Inhibitors in Preclinical Models.

ABSTRACT:

Abstract

Kirsten rat sarcoma (KRAS) is a potent oncogenic driver that results in the downstream hyperactivation of MAPK signaling while simultaneously increasing replication stress (RS) and accumulation of DNA damage. KRASG12C mutations are common and targetable alterations. Therapeutic inhibition of KRASG12C and eventual resistance to these inhibitors are also known to drive RS and DNA damage through adaptive mechanisms that maintain addiction to high MAPK signaling. High levels of RS result in a stronger reliance on cell-cycle checkpoints, thereby introducing a vulnerability to inhibition of cell-cycle checkpoint regulators such as the WEE1 kinase. This provides a rationale for combining azenosertib, a novel, selective, and orally bioavailable WEE1 inhibitor, with KRASG12C inhibi

SUBMITTER: Jameson NM 

PROVIDER: S-EPMC11795354 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature