Combined inhibition of the cell cycle related proteins Wee1 and Chk1/2 induces synergistic anti-cancer effect in melanoma

Abstract

BackgroundMalignant melanoma has an increasing incidence rate and the metastatic disease is notoriously resistant to standard chemotherapy. Loss of cell cycle checkpoints is frequently found in many cancer types and makes the cells reliant on compensatory mechanisms to control progression. This feature may be exploited in therapy, and kinases involved in checkpoint regulation, such as Wee1 and Chk1/2, have thus become attractive therapeutic targets.MethodsIn the present study we combined a Wee1 inhibitor (MK1775) with Chk1/2 inhibitor (AZD7762) in malignant melanoma cell lines grown in vitro (2D and 3D cultures) and in xenografts models.ResultsOur in vitro studies showed that combined inhibition of Wee1 and Chk1/2 synergistically decreased viability and increased apoptosis (cleavage of caspase 3 and PARP), which may be explained by accumulation of DNA-damage (increased expression of γ-H2A.X) - and premature mitosis of S-phase cells. Compared to either inhibitor used as single agents, combined treatment reduced spheroid growth and led to greater tumour growth inhibition in melanoma xenografts.ConclusionsThese data provide a rationale for further evaluation of the combination of Wee1 and Chk1/2 inhibitors in malignant melanoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1474-8) contains supplementary material, which is available to authorized users.

G2-checkpoint targeting and radiosensitization of HPV/p16-positive HNSCC cells through the inhibition of Chk1 and Wee1

“…Since the primary clinical necessity in HPV(+) HNSCC currently is to safely deintensify treatment, dual inhibition with reduced doses may be a viable approach but as a new regimen would need to be carefully studied in clinical trials focusing on both toxicity and efficacy. A number of recent publications have reported synergistic effects when combining Chk1 and Wee1 inhibition in cells of various tumor entities in vitro and in xenograft models, and some also reported an activation of Chk1 upon Wee1 inhibition [25][26][27][28][29][30][31][32]. Dual inhibition induced replication arrest and DNA damage, apoptosis, premature mitosis and a reduction of proliferation and viability.…”

Targeting the WEE1 kinase as a molecular targeted therapy for gastric cancer

“…In previous studies, AZD1775 has been shown to have a synergistic effect in DNA damage–based therapeutics by inducing unscheduled mitosis and eventually resulting in apoptosis in various cancers, such as melanoma, glioblastoma, and pancreatic cancer [28–30]. We also assessed the clinical potential of AZD1775 when combined with anti-cancer drugs, such as 5-FU (a DNA damage agent) and Paclitaxel (a mitotic inhibitor).…”

Reversal of cisplatin resistance by inhibiting PI3K/Akt signal pathway in human lung cancer cells

“…To solve this vexing drug resistance problem, combination therapy has been the solution over the last two decades, owing to their synergistic effects seen in some trials [4][5][6]. Although drug resistance is a common phenomenon in chemotherapy, the puzzling mechanism involving complicated signaling pathways is not entirely clear.…”