Targeting Wee1 kinase as a therapeutic approach in Hematological Malignancies

Abstract

Hematologic malignancies include various diseases that develop from hematopoietic stem cells of bone marrow or lymphatic organs. Currently, conventional DNA-damage-based chemotherapy drugs are approved as standard therapeutic regimens for these malignancies. Although many improvements have been made, patients with relapsed or refractory hematological malignancies have a poor prognosis. Therefore, novel and practical therapeutic approaches are required for the treatment of these diseases. Interestingly several studies have shown that targeting Wee1 kinase in the Hematological malignancies, including AML, ALL, CML, CLL, DLBCL, BL, MCL, etc., can be an effective therapeutic strategy. It plays an essential role in regulating the cell cycle process by abrogating the G2–M cell-cycle checkpoint, which provides time for DNA damage repair before mitotic entry. Consistently, Wee1 overexpression is observed in various Hematological malignancies. Also, in healthy normal cells, repairing DNA damages occurs due to G1-S checkpoint function; however, in the cancer cells, which have an impaired G1–S checkpoint, the damaged DNA repair process depends on the G2–M checkpoint function. Thus, Wee1 inhibition could be a promising target in the presence of DNA damage in order to potentiate multiple therapeutic drugs. This review summarized the potentials and challenges of Wee1 inhibition combined with other therapies as a novel effective therapeutic strategy in Hematological malignancies.

Introduction

Hematological malignancies include various malignant transformations originating from the blood, bone marrow, and lymphatic system. Three major types of these malignancies are leukemia, lymphoma, and multiple myeloma [1]. Current treatment of these diseases includes chemotherapy, radiotherapy, stem cell transplantation, and immunotherapy. However, due to the low specificity and high toxicity, the utility of chemotherapeutic drugs for Hematological malignancies is limited [2,3]. Thereby, there is a striking necessity to improve the efficacy and activity of conventional chemotherapeutic drugs.

Studies have shown that the cell cycle checkpoints play a critical role in malignant cells ' fate in exposure to anticancer treatments [4]. Furthermore, a genome-wide functional screen among the proteins in Dependency Map (DepMap) portal (www.depmap.org) and Oncomine database (www.Oncomine.org) demonstrates Wee1 kinase overexpression in the malignant cells compared to the normal cells. According to data from the DepMap site, liquid tumor cell lines are more sensitive to blockade of the Wee1 than solid tumor cell lines. Among hematopoietic cancer cell lines, the LOUCY cell line (related to ALL) is the most sensitive and the MLMA cell line (related to hairy cell leukemia) is the most resistant cell line to blockade of the Wee1. Also, among the solid tumor cell lines, CPCN cell line (related to SCLC disease) is the most sensitive and PCL15A cell line (related to head and neck cancer) is the most resistant cell line. Wee1, as a critical G2-M and G1-S checkpoints kinase, regulates cellular fate decisions consisting of progression, arrest, or apoptosis induction in the cell cycle process [5,6]. In response to the presence of DNA damage, Wee1-inhibitory phosphorylation of cyclin-dependent kinase 1 (CDK1) results in delay in the cell cycle progression [7], which provides time for DNA-damage repair, thus enable malignant cells to complete the cell cycle process by achieving sufficient genomic integrity [8]. In this regard, it has been demonstrated that genetic or pharmacologic inhibition of Wee1, together with anticancer treatments, inhibits more proliferation and induces apoptosis in malignant cell lines and primary patient samples, which validated the Wee1 kinase targeting potential as a therapeutic approach in Hematological malignancies [9]. This efficacy enhancement is due to abrogated cell cycle arrest that enforces mitosis entry in the cells harboring DNA damages and induces apoptosis in mitotic catastrophe process [[10], [11], [12]]. Thus, there is a rationale for targeting Wee1 to enhance the efficacy of conventional treatments that act by DNA damage induction [13].

The potent WEE1 inhibitor AZD1775 has advanced to clinical trials in combination with DNA-damaging agents such as carboplatin, cisplatin, docetaxel, 5-fluorouracil, gemcitabine, irinotecan, paclitaxel, pemetrexed, temozolomide, topotecan, or irradiation in various cancer types [[14], [15], [16], [17]]. Current clinical data in many cancer types with different genetic abnormalities support a combination of AZD1775 with DNA damaging agents. In addition, it has been demonstrated that AZD1775 can enhance the antitumor efficacy of anticancer therapeutics. This diverse effectiveness demonstrates that the action of AZD1775 may be dependent on a variety of cellular mechanisms [18].

In recent years, several studies devoted to improving these patients' therapy have led to the development of novel combined Wee1 inhibition and conventional treatments [9,[19], [20], [21], [22], [23]] (Table 1, Table 2, Table 3). This review describes current studies on Wee1 inhibition as a targeted therapy combined with other available treatments and limitations and potential advantages of these combination approaches to treat various types of Hematological malignancies, which hopefully will translate soon into a benefit to clinical practice in oncology.