Cyclin Dependent Kinases (CDKs) are closely connected to the regulation of cell cycle progression, having been first identified as the kinases able to drive cell division. In reality, the human genome contains 20 different CDKs, which can be divided in at least three different sub-family with different functions, mechanisms of regulation, expression patterns and subcellular localization. Most of these kinases play fundamental roles the normal physiology of eucaryotic cells; therefore, their deregulation is associated with the onset and/or progression of multiple human disease including but not limited to neoplastic and neurodegenerative conditions. Here, we describe the functions of CDKs, categorized into the three main functional groups in which they are classified, highlighting the most relevant pathways that drive their expression and functions. We then discuss the potential roles and deregulation of CDKs in human pathologies, with a particular focus on cancer, the human disease in which CDKs have been most extensively studied and explored as therapeutic targets. Finally, we discuss how CDKs inhibitors have become standard therapies in selected human cancers and propose novel ways of investigation to export their targeting from cancer to other relevant chronic diseases. We hope that the effort we made in collecting all available information on both the prominent and lesser-known CDK family members will help in identify and develop novel areas of research to improve the lives of patients affected by debilitating chronic diseases.

PARP inhibitors (PARPi) represent a game-changing treatment for patients with ovarian cancer with tumors deficient for the homologous recombination (HR) pathway treated with platinum (Pt)–based therapy. PARPi exert their cytotoxic effect by both trapping PARP1 on the damaged DNA and by restraining its enzymatic activity (PARylation). How PARP1 is recruited and trapped at the DNA damage sites and how resistance to PARPi could be overcome are still matters of investigation. Here, we described PARP1 as a substrate of the deubiquitinase USP1. At molecular level, USP1 binds PARP1 to remove its K63-linked polyubiquitination and controls PARP1 chromatin trapping and PARylation activity, regulating sensitivity to PARPi. In both Pt/PARPi-sensitive and -resistant cells, USP1/PARP1 combined blockade enhances replicative stress, DNA damage, and cell death. Our work dissected the biological interaction between USP1 and PARP1 and recommended this axis as a promising and powerful therapeutic choice for not only sensitive but also chemoresistant patients with ovarian cancer irrespective of their HR status.

Epithelial ovarian cancer (EOC) is a highly lethal disease characterized by a high rate of platinum (PT)-resistant recurrence. Dysregulation of transcriptional and alternative splicing (AS) has been suggested as a possible mechanism of PT resistance involving transcriptional cyclin-dependent kinases (CDKs). We report that pharmacological CDK12/CDK13 inhibition (CDK12i) synergistically enhances PT-induced cytotoxicity in a large number of PT-sensitive and PT-resistant EOC models. CDK12i effectively delayed the emergence of PT-resistant recurrences in vitro and in vivo. Acquired resistance to CDK12i enhanced PT sensitivity, revealing a therapeutically exploitable vulnerability to PT. CDK12i strongly reshapes transcriptional elongation and RNA processing, impacting multiple categories of AS, with marked enrichment of transcripts involved in the DNA damage repair (DDR) pathway. We proved that CDK12 interacts with the splicing master regulator SFPQ/p54 ^nrb complex, driving its distribution in transcriptional condensates. The p54 ^nrb subunit of the complex is required for the CDK12-SFPQ interaction and to ensure splicing reprogramming and CDK12i-induced cytotoxicity in all the EOC models tested. The use of CT7439, a novel clinical-grade CDK12i, which is now in phase I/II clinical trials, confirmed the therapeutic potential of CDK12i, either as monotherapy or in combination with PT. These findings emphasize that the therapeutic potential of CDK12i extends beyond DDR regulation, encompassing a critical role in RNA processing and AS. This dual impact affects EOC survival and may provide a novel, clinically relevant therapeutic strategy for hard-to-treat PT-resistant patients for whom effective treatment options remain limited.

This study aimed to identify risk factors for major postoperative complications (TMM) and their impact on overall survival in patients aged ≥80 years undergoing lung cancer surgery, a group at increased risk of morbidity. A total of 88 patients aged ≥80 years who underwent anatomical lung resections were retrospectively analyzed. Postoperative complications were classified into minor or no complications (TMM 0–2) and major (TMM ≥ 3) complications. Logistic regression analysis was performed to identify independent predictors of major complications. Kaplan–Meier estimates were used to measure overall survival. Major complications occurred in 24 patients (27.3%). Multivariable regression analysis identified perioperative blood transfusion as an independent risk factor for major complications (p = 0.0009). Patients with major complications exhibited significantly reduced overall survival (p = 0.0009). Subgroup analysis revealed that patients who underwent minimally invasive surgery had significantly better survival (p = 0.01). Moreover, perioperative transfusion correlated with diminished overall survival (p = 0.0027). In patients aged ≥80 years undergoing lung resections, the occurrence of major postoperative complications is associated with significantly impaired survival. Minimally invasive surgical approaches and blood conservation strategies may mitigate complications and enhance long-term outcomes in this high-risk group.