The activity of the Salt inducible kinase 2 (SIK2), a member of the AMP-activated protein kinase (AMPK)-related kinase family, has been linked to several biological processes that maintain cellular and energetic homeostasis. SIK2 is overexpressed in several cancers, including ovarian cancer, where it promotes the proliferation of metastases. Furthermore, as a centrosome kinase, SIK2 has been shown to regulate the G2/M transition, and its depletion sensitizes ovarian cancer to paclitaxel-based chemotherapy. Here, we report the consequences of SIK2 inhibition on mitosis and synergies with paclitaxel in ovarian cancer using a novel and selective inhibitor, MRIA9. We show that MRIA9-induced inhibition of SIK2 blocks the centrosome disjunction, impairs the centrosome alignment, and causes spindle mispositioning during mitosis. Furthermore, the inhibition of SIK2 using MRIA9 increases chromosomal instability, revealing the role of SIK2 in maintaining genomic stability. Finally, MRIA9 treatment enhances the sensitivity to paclitaxel in 3D-spheroids derived from ovarian cancer cell lines and ovarian cancer patients. Our study suggests selective targeting of SIK2 in ovarian cancer as a therapeutic strategy for overcoming paclitaxel resistance.

Ovarian cancer (OC) accounts for approximately 4% of cancer deaths in women worldwide and is the deadliest gynecologic malignancy. High-grade serous ovarian cancer (HGSOC) is the most predominant ovarian cancer, in which BRCA1/2 gene mutation ranges from 3 to 27%. PARP inhibitors (PARPi) have shown promising results as a synthetically lethal therapeutic approach for BRCA mutant and recurrent OC in clinical use. However, emerging data indicate that BRCA-deficient cancers may be resistant to PARPi, and the mechanisms of this resistance remain elusive. We found that amplification of KRAS likely underlies PARPi resistance in BRCA2-deficient HGSOC. Our data suggest that PLK1 inhibition restores sensitivity to PARPi in HGSOC with KRAS amplification. The sequential combination of PLK1 inhibitor (PLK1i) and PARPi drastically reduces HGSOC cell survival and increases apoptosis. Furthermore, we were able to show that a sequential combination of PLK1i and PARPi enhanced the cellular apoptotic response to carboplatin-based chemotherapy in KRAS-amplified resistant HGSOC cells and 3D spheroids derived from recurrent ovarian cancer patients. Our results shed new light on the critical role of PLK1 in reversing PARPi resistance in KRAS-amplified HGSOC, and offer a new therapeutic strategy for this class of ovarian cancer patients where only limited options currently exist.

Ovarian cancer is one of the most lethal gynecological cancers worldwide, with approximately 70% of cases diagnosed in advanced stages. This late diagnosis results from the absence of early warning symptoms and is associated with an unfavorable prognosis. A standard treatment entails a combination of primary chemotherapy with platinum and taxane agents. Tumor recurrence following first-line chemotherapy with Carboplatin and Paclitaxel is detected in 80% of advanced ovarian cancer patients, with disease relapse occurring within 2 years of initial treatment. Platinum-resistant ovarian cancer is one of the biggest challenges in treating patients. Second-line treatments involve PARP or VEGF inhibitors. Identifying novel biomarkers and resistance mechanisms is critical to overcoming resistance, developing newer treatment strategies, and improving patient survival. In this study, we have determined that low Caspase-8 expression in ovarian cancer patients leads to poor prognosis. High-Grade Serous Ovarian Cancer (HGSOC) cells lacking Caspase-8 expression showed an altered composition of the RNA Polymerase II-containing transcriptional elongation complex leading to increased transcriptional activity. Caspase-8 knockout cells display increased BRD4 expression and CDK9 activity and reduced sensitivities to Carboplatin and Paclitaxel. Based on our work, we are proposing three potential therapeutic approaches to treat advanced ovarian cancer patients who exhibit low Caspase-8 expression and resistance to Carboplatin and/or Paclitaxel—combinations of (1) Carboplatin with small-molecule BRD4 inhibitors; (2) Paclitaxel with small-molecule BRD4 inhibitors, and (3) small-molecule BRD4 and CDK9 inhibitors. In addition, we are also proposing two predictive markers of chemoresistance—BRD4 and pCDK9.

Background: Robotic-assisted surgery (RAS) has progressively expanded in gynecologic practice. Although its technical advantages are recognized, its economic sustainability and equitable accessibility remain debated. Methods: This clinical update provides a critical narrative review of current evidence on RAS in gynecology, integrating data on clinical outcomes, cost-effectiveness, diffusion patterns, and health equity across different healthcare settings. Results: In both benign and oncologic indications, RAS demonstrates consistent perioperative advantages over open surgery, including reduced blood loss, shorter hospital stay, and lower conversion rates. In routine cases, outcomes are largely comparable to conventional laparoscopy. However, robotic approaches appear particularly beneficial in complex scenarios, such as obesity, advanced malignancy, and technically demanding procedures. Economic evidence is heterogeneous. Short-term hospital-based studies report higher direct costs for RAS, especially in benign surgery. Conversely, cost–utility models in oncologic settings suggest that RAS may achieve acceptable cost-effectiveness when long-term outcomes, quality-adjusted life years, and institutional volume are considered. Accessibility remains strongly influenced by reimbursement policies, procedural volume, infrastructure, and workforce training. In the absence of structured reimbursement frameworks, robotic surgery may contribute to socioeconomic and geographic disparities. Conclusions: RAS represents an important component of modern gynecologic surgery, particularly in high-complexity and high-risk cases in which its technical advantages may translate into meaningful perioperative benefit. Its long-term sustainability depends on appropriate patient selection, institutional volume, reimbursement models, and health system organization. Future research incorporating long-term and societal economic perspectives is required to support balanced and equitable implementation.

Background: Abdominal hysterectomy has been largely replaced by minimally invasive surgery. Nevertheless, in some situations, a minimally invasive intervention must be converted to laparotomy. Factors associated with conversion to laparotomy are still a matter of debate. Objective: The aim of this study was to evaluate the clinicopathological factors associated with the conversion of laparoscopic hysterectomy to laparotomy. Material and Methods: The risk factors for conversion of a preplanned laparoscopic procedure to laparotomy were retrospectively evaluated in 441 patients undergoing a hysterectomy for a benign indication between 2016 and 2020. Associations between the clinical factors were analysed using Pearson’s chi-square and Fisher’s exact test, and predictive values for conversion were assessed through multivariate logistic regression. Result: Conversion occurred in 32 (7.3%) of the cases. Significant differences were detected for uterus weight (576.9gr vs 174.6gr, p<0.001), myoma size (7.0 cm vs. 1.8 cm, p<0.001), and presence of triple diagnosis consisting of leiomyoma, adenomyosis uteri, and pathological adnexal findings (p<0.013). The conversion resulted in prolonged surgery time (181.6 min vs. 119.6 min, p<0.001) and hospital stay (4.0 vs. 3.1 days, p<0.001), as well as an increased rate of wound infection (15.6% vs. 3.4%, p<0.001). A 10g increase in uterus weight raised the risk of conversion by 7.0%, and a 1cm increase in myoma diameter by 7.3%, while adnexal pathologies and extensive adhesions increased the odds of conversion to laparotomy threefold (ORs of 3.2, 1.09-9.6 and 3.6, 1.3-10.0, respectively). Conclusion: Uterus weight, myoma size, the coexistence of pathological adnexal findings, and non-physiological adhesions are independent risk factors for conversion. What is new? This study provides data regarding the risk and factors increasing this risk for conversion to laparotomy during laparoscopic hysterectomy.