WEE1 Inhibition Enhances Anti-Apoptotic Dependency as a Result of Premature Mitotic Entry and DNA Damage

Abstract

Genomically unstable cancers are dependent on specific cell cycle checkpoints to maintain viability and prevent apoptosis. The cell cycle checkpoint protein WEE1 is highly expressed in genomically unstable cancers, including diffuse large B-cell lymphoma (DLBCL). Although WEE1 inhibition effectively induces apoptosis in cancer cells, the effect of WEE1 inhibition on anti-apoptotic dependency is not well understood. We show that inhibition of WEE1 by AZD1775 induces DNA damage and pre-mitotic entry in DLBCL, thereby enhancing dependency on BCL-2 and/or MCL-1. Combining AZD1775 with anti-apoptotic inhibitors such as venetoclax (BCL-2i) or S63845 (MCL-1i) enhanced sensitivity in a cell-specific manner. In addition, we demonstrate that both G2/M cell cycle arrest and DNA damage induction put a similar stress on DLBCL cells, thereby enhancing anti-apoptotic dependency. Therefore, genotoxic or cell cycle disrupting agents combined with specific anti-apoptotic inhibitors may be very effective in genomic unstable cancers such as DLBCL and therefore warrants further clinical evaluation.

Tracking the Genetic Susceptibility Background of B-Cell Non-Hodgkin’s Lymphomas from Genome-Wide Association Studies

“…Furthermore, there is an unmet need to translate theoretical information into clinical practice which has been done, for example, with the use of adavosertib, an WEE1 inhibitor, to increase response in DLBCL patients. In line with this, the incorporation of single-cell sequencing technology can help identify B-cell stages (dark/light zone) and cell cycle phases to further amplify the possibilities for therapy options [ 17 , 46 , 83 ].…”

“…They further evaluated these targets using inhibiting drugs (AZD1775 for WEE1 and olaparib for PARP1) on different cell lines finding increased cytotoxic effects. Furthermore, a later study from the same group led to the discovery that combined WEE1 and anti-apoptotic protein inhibition enhances premature mitotic entry and DNA damage which may benefit genomic unstable DLBCL cells [ 17 , 46 ]. Moreover, there are over 20 clinical trials exploring adavosertib, the most potent and selective WEE1 inhibitor, as a single agent or in combination for different indications ( , October 2020).…”

A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target

“…Moreover, strong synergism has been observed by combining adavosertib with small molecules, including DDR-related inhibitors (CDK2 [ 89 ], CDK4-6 [ 149 ], CHK1 [ 103 , 140 – 142 ], ATM [ 132 – 135 ], AURORA A [ 147 ], PARP1 [ 144 ], SIRT1 [ 148 ] inhibitors), histone deacetylase (HDAC) inhibitors [ 41 , 130 , 131 ], tyrosine kinase inhibitors (BCR-ABL1 inhibitors [ 35 ]), anti-apoptotic protein inhibitors (BCL2 and MCL1 inhibitors [ 143 ]), mTOR inhibitor [ 136 – 139 ], and proteasome inhibitors [ 36 ].…”

Targeted Therapies for Pancreatic Cancer: Overview of Current Treatments and New Opportunities for Personalized Oncology

“…Preclinical evidence has indicated that Wee1 inhibitors show synergistic effects when combined with histone deacetylase (HDAC) inhibitors [ 49 ], proteasome inhibitors [ 50 ], tyrosine kinase inhibitors [ 51 ], anti-apoptotic protein inhibitors (enhance dependency on BCL-2 and/or MCL-1 inhibition) [ 52 ], and mammalian (or mechanic) target of rapamycin (mTOR) inhibitors [ 53 ]. This latter study is particularly noteworthy for PCa as mTOR inhibition was found to synergize with Wee1 inhibition in KRAS mutant tumors.…”