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

Abstract

The inhibition of the DNA damage response (DDR) pathway in the treatment of cancer has recently gained interest, and different DDR inhibitors have been developed. Among them, the most promising ones target the WEE1 kinase family, which has a crucial role in cell cycle regulation and DNA damage identification and repair in both nonmalignant and cancer cells. This review recapitulates and discusses the most recent findings on the biological function of WEE1/PKMYT1 during the cell cycle and in the DNA damage repair, with a focus on their dual role as tumor suppressors in nonmalignant cells and pseudo-oncogenes in cancer cells. We here report the available data on the molecular and functional alterations of WEE1/PKMYT1 kinases in both hematological and solid tumors. Moreover, we summarize the preclinical information on 36 chemo/radiotherapy agents, and in particular their effect on cell cycle checkpoints and on the cellular WEE1/PKMYT1-dependent response. Finally, this review outlines the most important pre-clinical and clinical data available on the efficacy of WEE1/PKMYT1 inhibitors in monotherapy and in combination with chemo/radiotherapy agents or with other selective inhibitors currently used or under evaluation for the treatment of cancer patients.

Keywords: Cell cycle; DNA repair; PKMYT1; Pseudo-oncogene; Tumor suppressor; WEE1; WEE1 family kinases.

Fig. 1

WEE1 and PKMYT1 biological functions. a Schematic representation of WEE1 and PKMYT1 involvement in cell cycle checkpoints. WEE1 regulates the activity of both CDK1 and CDK2 kinases (trough phosphorylation of Tyr15) and is involved in the regulation of intra-S, G2/M, and M phase cell cycle checkpoints. PKMYT1 selectively regulates CDK1 (through phosphorylation of Tyr15 and Thr14) and is plays a role in the G2/M phase checkpoint. b Schematic representation of the regulation of MUS81-EME1/2 endonuclease complexes by WEE1 during S and G2/M cell cycle phases. By inhibiting CDK2 or CDK1, WEE1 prevents MUS81 activation and the generation of DNA damages during S phase, and chromosomes pulverization during G2/M phase

Fig. 2

WEE1 family proteins role as tumor suppressors or pseudo-oncogenes in non-malignant and cancer cells

Fig. 3

WEE1 and PKMYT1 mutations and copy number alterations (CNAs) in cancer. a Frequency of patients with WEE1 or b PKMYT1 gene mutations across cancers from TCGA cohorts. c Distribution of mutations according to the WEE1 and d PKMYT1 amino acid (aa) sequence and protein domains (WEE1 transcript ENST00000450114, 646 aa; PKMYT1 transcript ENST00000262300, 499 aa). e Frequency of patients with copy number gain or loss in WEE1 or f PKMYT1 across cancers (https://portal.gdc.cancer.gov; ACC adrenocortical carcinoma, BLCA bladder urothelial carcinoma, BRCA breast invasive carcinoma, CESC cervical squamous cell carcinoma and endocervical adenocarcinoma, COAD colon adenocarcinoma, CHOL cholangiocarcinoma, DLBC diffuse large B cell lymphoma, ESCA esophageal carcinoma, GBM glioblastoma multiforme, HNSC head and neck squamous cell carcinoma, KICH kidney chromophobe, KIRK kidney renal clear cell carcinoma, KIRP kidney renal papillary cell carcinoma, LGG brain lower grade glioma, LIHC liver hepatocellular carcinoma, LUAD lung adenocarcinoma, LUSC lung squamous cell carcinoma, MESO mesothelioma, OV ovarian serous cystadenocarcinoma, PAAD pancreatic adenocarcinoma, PCPG pheochromocytoma and paraganglioma, PRAD prostate adenocarcinoma, READ rectum adenocarcinoma, SARC sarcoma, SKCM skin cutaneous melanoma, STAD stomach adenocarcinoma, TGCT testicular germ cell tumors, THYM thymoma, UCS uterine carcinosarcoma, UCEC uterine corpus endometrial carcinoma)

Fig. 4

Mechanism of action of WEE1/PKMYT1 inhibitors for the treatment of cancer cells. a Schematic representation of WEE1/PKMYT1 inhibition as monotherapy. In cancer cells, oncogenes promote high rate of proliferation, replication stress and the over-expression of WEE1/PKMYT1 kinases. In this scenario, cancer cells need WEE1 and PKMYT1 to sustain replication stress and proliferation. The inhibition of WEE1/PKMYT1 results in the accumulation of DNA damages, the increase of genetic instability and induction of apoptosis. b Schematic representation of WEE1/PKMYT1 inhibition in combination with DNA damaging agents. Cancer cells respond to DNA damages by activating WEE1/PKMYT1 kinases. The inhibition of WEE1/PKMYT1 enhances the cytotoxicity of DNA damaging agents by inhibiting DNA repair and promoting cell cycle progression even in the presence of DNA damages. Therefore, cancer cells accumulate massive DNA damages until a point of no return