Active growth signaling promotes senescence and cancer cell sensitivity to CDK7 inhibition

Tumor growth is driven by continued cellular growth and proliferation. Cyclin-dependent kinase 7’s (CDK7) role in activating mitotic CDKs and global gene expression makes it therefore an attractive target for cancer therapies. However, what makes cancer cells particularly sensitive to CDK7 inhibition (CDK7i) remains unclear. Here, we address this question. We show that CDK7i, by samuraciclib, induces a permanent cell-cycle exit, known as senescence, without promoting DNA damage signaling or cell death. A chemogenetic genome-wide CRISPR knockout screen identified that active mTOR (mammalian target of rapamycin) signaling promotes samuraciclib-induced senescence. mTOR inhibition decreases samuraciclib sensitivity, and increased mTOR-dependent growth signaling correlates with sensitivity in cancer cell lines. Reverting a growth-promoting mutation in PIK3CA to wild type decreases sensitivity to CDK7i. Our work establishes that enhanced growth alone promotes CDK7i sensitivity, providing an explanation for why some cancers are more sensitive to CDK inhibition than normally growing cells

Network Rewiring of Homologous Recombination Enzymes during Mitotic Proliferation and Meiosis.

Homologous recombination (HR) is essential for high-fidelity DNA repair during mitotic proliferation and meiosis. Yet, context-specific modifications must tailor the recombination machinery to avoid (mitosis) or enforce (meiosis) the formation of reciprocal exchanges-crossovers-between recombining chromosomes. To obtain molecular insight into how crossover control is achieved, we affinity purified 7 DNA-processing enzymes that channel HR intermediates into crossovers or noncrossovers from vegetative cells or cells undergoing meiosis. Using mass spectrometry, we provide a global characterization of their composition and reveal mitosis- and meiosis-specific modules in the interaction networks. Functional analyses of meiosis-specific interactors of MutLγ-Exo1 identified Rtk1, Caf120, and Chd1 as regulators of crossing-over. Chd1, which transiently associates with Exo1 at the prophase-to-metaphase I transition, enables the formation of MutLγ-dependent crossovers through its conserved ability to bind and displace nucleosomes. Thus, rewiring of the HR network, coupled to chromatin remodeling, promotes context-specific control of the recombination outcome

Mechanisms of sensitivity and resistance to CDK4/CDK6 inhibitors in hormone receptor-positive breast cancer treatment

Cell cycle dysregulation is a hallmark of cancer that promotes eccessive cell division. Cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) are key molecules in the G1-to-S phase cell cycle transition and are crucial for the onset, survival, and progression of breast cancer (BC). Small-molecule CDK4/CDK6 inhibitors (CDK4/6i) block phosphorylation of tumor suppressor Rb and thus restrain susceptible BC cells in G1 phase. Three CDK4/6i are approved for the first-line treatment of patients with advanced/metastatic hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) BC in combination with endocrine therapy (ET). Though this has improved the clinical outcomes for survival of BC patients, there is no established standard next-line treatment to tackle drug resistance. Recent studies suggest that CDK4/6i can modulate other distinct effects in both BC and breast stromal compartments, which may provide new insights into aspects of their clinical activity. This review describes the biochemistry of the CDK4/6-Rb-E2F pathway in HR+ BC, then discusses how CDK4/6i can trigger other effects in BC/breast stromal compartments, and finally outlines the mechanisms of CDK4/6i resistance that have emerged in recent preclinical studies and clinical cohorts, emphasizing the impact of these findings on novel therapeutic opportunities in BC

UTJECAJ RAZLIČITE HRANE ZA KVASCE NA AROMATSKI PROFIL VINA CABERNET SAUVIGNON

Ovim radom nastoji se utvrditi koliki utjecaj na kinetiku alkoholne fermentacije, fizikalno – kemijske parametre i aromatski profil ima dodatak različitih hraniva za kvasce. Prvi dio rada odnosi se na arome, koje smo podijelili i obradili kao primarne, sekundarne i tercijarne. Drugi dio rada opisuje sortu Cabernet Sauvignon. Treći dio rada obrađuje dušične spojeve sa naglaskom na specifičnost i značajnost aminokiselina u moštu i vinu. Specifičnost odabranih hrana za kvasce je njen aminokiselinski sastav, za koje se nastoji uvidjeti ima li utjecaj na različite parametre u vinu. Radi se o hrani za kvasce talijanskog proizvođača AEB, pod imenom FERMOPLUS TROPICAL i FERMOPLUS CH, a kao kontrola koristio se ENOVIT. Vino koje je upotrebljavano je Cabernet Sauvignon, svjetski poznat crni kultivar, zanimljivog aromatskog profila. Zadatak je protekao na način da smo pojedinačni masulj Cabernet Sauvignon – a nakon unifikacije masulja raspodijelili u tri inoks tanka, i u svaki tank je dodana različita hrana za kvasce. Najbolji rezultat smo dobili korištenjem hrane FERMOPLUS CH. Promjene su bile vidljive samo u aromatskom profilu, dok kod kinetike alkoholne fermentacije i fizikalno - kemijskih parametara nisu uočene razlike

UTJECAJ RAZLIČITE HRANE ZA KVASCE NA AROMATSKI PROFIL VINA CABERNET SAUVIGNON

Ovim radom nastoji se utvrditi koliki utjecaj na kinetiku alkoholne fermentacije, fizikalno – kemijske parametre i aromatski profil ima dodatak različitih hraniva za kvasce. Prvi dio rada odnosi se na arome, koje smo podijelili i obradili kao primarne, sekundarne i tercijarne. Drugi dio rada opisuje sortu Cabernet Sauvignon. Treći dio rada obrađuje dušične spojeve sa naglaskom na specifičnost i značajnost aminokiselina u moštu i vinu. Specifičnost odabranih hrana za kvasce je njen aminokiselinski sastav, za koje se nastoji uvidjeti ima li utjecaj na različite parametre u vinu. Radi se o hrani za kvasce talijanskog proizvođača AEB, pod imenom FERMOPLUS TROPICAL i FERMOPLUS CH, a kao kontrola koristio se ENOVIT. Vino koje je upotrebljavano je Cabernet Sauvignon, svjetski poznat crni kultivar, zanimljivog aromatskog profila. Zadatak je protekao na način da smo pojedinačni masulj Cabernet Sauvignon – a nakon unifikacije masulja raspodijelili u tri inoks tanka, i u svaki tank je dodana različita hrana za kvasce. Najbolji rezultat smo dobili korištenjem hrane FERMOPLUS CH. Promjene su bile vidljive samo u aromatskom profilu, dok kod kinetike alkoholne fermentacije i fizikalno - kemijskih parametara nisu uočene razlike

VENLAFAXINE – QUETIAPINE COMBINATION IN THE TREATMENT OF COMPLICATED CLINICAL PICTURE OF ENDURING PERSONALITY CHANGES FOLLOWING PTSD IN COMORBIDITY WITH PSYCHOTIC DEPRESSION

PTSD is a complex disorder, which frequently occurs in comorbidity with anxious disorder, personality disorder, addiction or substance abuse disorder, depressive disorder with or without psychotic symptoms and psychotic disorder. PTSD symptoms may result from deregulation of several different neurotransmitter systems. Pharmacotherapy of PTSD depends on clinical features and the presence of comorbid disorders. Pharmacotherapy of PTSD involves use of anxiolytics, adrenergic receptor antagonists, antidepressants, anticonvulsants and novel antipsychotics. Serotoninergic effect of antidepressants is not only effective in treating depression, but also appears to be helpful in PTSD treatment, particularly in reduction of intrusive symptoms, emotional reactivity, impulsiveness, aggression and suicidal ideation. Anypsychotics with serotoninergic-dopaminergic antagonism are being prescribed often in treatment of psychotic depression, while in PTSD treatment they are proved to be efficient in relieving intrusive symptoms and nightmares. Quetiapine as serotoninergic-dopaminergic antagonist is efficient in treatment of chronic insomnia as well as inreduction of aggressiveness. Considering PTSD refractoriness to therapy, high incidence of comorbidity and significant functional impairment, it is important to search for new psychopharmacological combinations in order to improve mental status of the patient. The paper presents 46 years old male patient with the diagnosis of Enduring personality changes following war PTSD (F62.0) in comorbidity with Recurrent depressive disorder with psychotic symptoms (F33.3), who was treated with combination of venlafaxine and quetiapine

A risk analysis of alpelisib-induced hyperglycemia in patients with advanced solid tumors and breast cancer

Abstract Background Hyperglycemia is an on-target effect of PI3Kα inhibitors. Early identification and intervention of treatment-induced hyperglycemia is important for improving management of patients receiving a PI3Kα inhibitor like alpelisib. Here, we characterize incidence of grade 3/4 alpelisib-related hyperglycemia, along with time to event, management, and outcomes using a machine learning model. Methods Data for the risk model were pooled from patients receiving alpelisib ± fulvestrant in the open-label, phase 1 X2101 trial and the randomized, double-blind, phase 3 SOLAR-1 trial. The pooled population (n = 505) included patients with advanced solid tumors (X2101, n = 221) or HR+/HER2− advanced breast cancer (SOLAR-1, n = 284). External validation was performed using BYLieve trial patient data (n = 340). Hyperglycemia incidence and management were analyzed for SOLAR-1. Results A random forest model identified 5 baseline characteristics most associated with risk of developing grade 3/4 hyperglycemia (fasting plasma glucose, body mass index, HbA1c, monocytes, age). This model was used to derive a score to classify patients as high or low risk for developing grade 3/4 hyperglycemia. Applying the model to patients treated with alpelisib and fulvestrant in SOLAR-1 showed higher incidence of hyperglycemia (all grade and grade 3/4), increased use of antihyperglycemic medications, and more discontinuations due to hyperglycemia (16.7% vs. 2.6% of discontinuations) in the high- versus low-risk group. Among patients in SOLAR-1 (alpelisib + fulvestrant arm) with PIK3CA mutations, median progression-free survival was similar between the high- and low-risk groups (11.0 vs. 10.9 months). For external validation, the model was applied to the BYLieve trial, for which successful classification into high- and low-risk groups with shorter time to grade 3/4 hyperglycemia in the high-risk group was observed. Conclusions A risk model using 5 clinically relevant baseline characteristics was able to identify patients at higher or lower probability for developing alpelisib-induced hyperglycemia. Early identification of patients who may be at higher risk for hyperglycemia may improve management (including monitoring and early intervention) and potentially lead to improved outcomes. Registration: ClinicalTrials.gov: NCT01219699 (registration date: October 13, 2010; retrospectively registered), ClinicalTrials.gov: NCT02437318 (registration date: May 7, 2015); ClinicalTrials.gov: NCT03056755 (registration date: February 17, 2017)

Active growth signaling promotes senescence and cancer cell sensitivity to CDK7 inhibition

Tumor growth is driven by continued cellular growth and proliferation. Cyclin-dependent kinase 7's (CDK7) role in activating mitotic CDKs and global gene expression makes it therefore an attractive target for cancer therapies. However, what makes cancer cells particularly sensitive to CDK7 inhibition (CDK7i) remains unclear. Here, we address this question. We show that CDK7i, by samuraciclib, induces a permanent cell-cycle exit, known as senescence, without promoting DNA damage signaling or cell death. A chemogenetic genome-wide CRISPR knockout screen identified that active mTOR (mammalian target of rapamycin) signaling promotes samuraciclib-induced senescence. mTOR inhibition decreases samuraciclib sensitivity, and increased mTOR-dependent growth signaling correlates with sensitivity in cancer cell lines. Reverting a growth-promoting mutation in PIK3CA to wild type decreases sensitivity to CDK7i. Our work establishes that enhanced growth alone promotes CDK7i sensitivity, providing an explanation for why some cancers are more sensitive to CDK inhibition than normally growing cells

Additional file 1 of A risk analysis of alpelisib-induced hyperglycemia in patients with advanced solid tumors and breast cancer

Additional file 1. Supplemental Appendix