Phosphoinositide 3-kinases (PI3K) and phosphoinositide 3-kinase-related protein kinases (PIKK) are two structurally related families of kinases that play vital roles in cell growth and DNA damage repair. Dysfunction of PIKK members and aberrant stimulation of the PI3K/AKT/mTOR signalling pathway are linked to a plethora of diseases including cancer. In recent decades, numerous inhibitors related to the PI3K/AKT/mTOR signalling have made great strides in cancer treatment, like copanlisib and sirolimus. Notably, most of the PIKK inhibitors (such as VX-970 and M3814) related to DNA damage response have also shown good efficacy in clinical trials. However, these drugs still require a suitable combination therapy to overcome drug resistance or improve antitumor activity. Based on the aforementioned facts, we summarised the efficacy of PIKK, PI3K, and AKT inhibitors in the therapy of human malignancies and the resistance mechanisms of targeted therapy, in order to provide deeper insights into cancer treatment.

• Klíčová slova
• AKT, PI3K, PIKK, anticancer therapy, inhibitors,
• MeSH
• 1-fosfatidylinositol-3-kinasa * metabolismus   terapeutické užití   MeSH
• fosfatidylinositol-3-kinasy metabolismus   MeSH
• inhibitory fosfoinositid-3-kinasy farmakologie   MeSH
• inhibitory proteinkinas farmakologie   terapeutické užití   MeSH
• lidé MeSH
• nádory * farmakoterapie   MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• TOR serin-threoninkinasy metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• 1-fosfatidylinositol-3-kinasa * MeSH
• fosfatidylinositol-3-kinasy MeSH
• inhibitory fosfoinositid-3-kinasy MeSH
• inhibitory proteinkinas MeSH
• protoonkogenní proteiny c-akt MeSH
• TOR serin-threoninkinasy MeSH

Cancer is the second leading cause of death globally. One of the main hallmarks in cancer is the functional deregulation of crucial molecular pathways via driver genetic events that lead to abnormal gene expression, giving cells a selective growth advantage. Driver events are defined as mutations, fusions and copy number alterations that are causally implicated in oncogenesis. Molecular analysis on tissues that have originated from a wide range of anatomical areas has shown that mutations in different members of several pathways are implicated in different cancer types. In recent decades, significant efforts have been made to incorporate this knowledge into daily medical practice, providing substantial insight towards clinical diagnosis and personalized therapies. However, since there is still a strong need for more effective drug development, a deep understanding of the involved signaling mechanisms and the interconnections between these pathways is highly anticipated. Here, we perform a systemic analysis on cancer patients included in the Pan-Cancer Atlas project, with the aim to select the ten most highly mutated signaling pathways (p53, RTK-RAS, lipids metabolism, PI-3-Kinase/Akt, ubiquitination, b-catenin/Wnt, Notch, cell cycle, homology directed repair (HDR) and splicing) and to provide a detailed description of each pathway, along with the corresponding therapeutic applications currently being developed or applied. The ultimate scope is to review the current knowledge on highly mutated pathways and to address the attractive perspectives arising from ongoing experimental studies for the clinical implementation of personalized medicine.

• Klíčová slova
• NGS, cancer patients, clinical implementation, molecular oncology, mutations, precision medicine, tumor,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

PURPOSE: A phase II study (ClinicalTrials.gov identifier: NCT00628251) showed activity of olaparib capsules versus pegylated liposomal doxorubicin in patients with germline BRCA-mutated platinum-resistant or partially platinum-sensitive relapsed ovarian cancer. We conducted a phase III trial (SOLO3) of olaparib tablets versus nonplatinum chemotherapy in patients with germline BRCA-mutated platinum-sensitive relapsed ovarian cancer who had received at least 2 prior lines of platinum-based chemotherapy. PATIENTS AND METHODS: In this randomized, open-label trial, patients were randomly assigned 2:1 to olaparib 300 mg twice a day or physician's choice single-agent nonplatinum chemotherapy (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan). The primary end point was objective response rate (ORR) in the measurable disease analysis set assessed by blinded independent central review (BICR). The key secondary end point was progression-free survival (PFS) assessed by BICR in the intent-to-treat population. RESULTS: Of 266 randomly assigned patients, 178 were assigned to olaparib and 88 to chemotherapy. In patients with measurable disease (olaparib, n = 151; chemotherapy, n = 72), the BICR-assessed ORR was significantly higher with olaparib than with chemotherapy (72.2% v 51.4%; odds ratio [OR], 2.53 [95% CI, 1.40 to 4.58]; P = .002). In the subgroup who had received 2 prior lines of treatment, the ORR was 84.6% with olaparib and 61.5% with chemotherapy (OR, 3.44 [95% CI, 1.42 to 8.54]). BICR-assessed PFS also significantly favored olaparib versus chemotherapy (hazard ratio, 0.62 [95% CI, 0.43 to 0.91]; P = .013; median, 13.4 v 9.2 months). Adverse events were consistent with the established safety profiles of olaparib and chemotherapy. CONCLUSION: Olaparib resulted in statistically significant and clinically relevant improvements in ORR and PFS compared with nonplatinum chemotherapy in patients with germline BRCA-mutated platinum-sensitive relapsed ovarian cancer who had received at least 2 prior lines of platinum-based chemotherapy.

• MeSH
• dospělí MeSH
• ftalaziny škodlivé účinky   terapeutické užití   MeSH
• geny BRCA1 * MeSH
• geny BRCA2 * MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru MeSH
• nádory vaječníků farmakoterapie   genetika   mortalita   MeSH
• piperaziny škodlivé účinky   terapeutické užití   MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• sloučeniny platiny terapeutické užití   MeSH
• zárodečné mutace * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• ftalaziny MeSH
• olaparib MeSH Prohlížeč
• piperaziny MeSH
• sloučeniny platiny MeSH

Cyclin-dependent kinase 12 (CDK12) phosphorylates the C-terminal domain of RNA polymerase II and is needed for the optimal transcription elongation and translation of a subset of human protein-coding genes. The kinase has a pleiotropic effect on the maintenance of genome stability, and its inactivation in prostate and ovarian tumours results in focal tandem duplications, a CDK12-unique genome instability phenotype. CDK12 aberrations were found in many other malignancies and have the potential to be used as biomarkers for therapeutic intervention. Moreover, the inhibition of CDK12 emerges as a promising strategy for treatment in several types of cancers. In this review, we summarize mechanisms that CDK12 utilizes for the regulation of gene expression and discuss how the perturbation of CDK12-sensitive genes contributes to the disruption of cell cycle progression and the onset of genome instability. Furthermore, we describe tumour-suppressive and oncogenic functions of CDK12 and its potential as a biomarker and inhibition target in anti-tumour treatments.

• Publikační typ
• časopisecké články MeSH

Cellular mechanisms that safeguard genome integrity are often subverted in cancer. To identify cancer-related genome caretakers, we employed a convergent multi-screening strategy coupled to quantitative image-based cytometry and ranked candidate genes according to multivariate readouts reflecting viability, proliferative capacity, replisome integrity, and DNA damage signaling. This unveiled regulators of replication stress resilience, including components of the pre-mRNA cleavage and polyadenylation complex. We show that deregulation of pre-mRNA cleavage impairs replication fork speed and leads to excessive origin activity, rendering cells highly dependent on ATR function. While excessive formation of RNA:DNA hybrids under these conditions was tightly associated with replication-stress-induced DNA damage, inhibition of transcription rescued fork speed, origin activation, and alleviated replication catastrophe. Uncoupling of pre-mRNA cleavage from co-transcriptional processing and export also protected cells from replication-stress-associated DNA damage, suggesting that pre-mRNA cleavage provides a mechanism to efficiently release nascent transcripts and thereby prevent gene gating-associated genomic instability.

• Klíčová slova
• ATR, R-loops, RNA:DNA hybrids, checkpoint activation, cleavage, gene gating, origin firing, polyadenylation, pre-mRNA processing, replication catastrophe, replication stress,
• MeSH
• aktivní transport - buněčné jádro MeSH
• DNA nádorová genetika   metabolismus   MeSH
• DNA vazebné proteiny MeSH
• HeLa buňky MeSH
• heteroduplexy nukleové kyseliny genetika   metabolismus   MeSH
• jaderné proteiny genetika   metabolismus   MeSH
• lidé MeSH
• messenger RNA biosyntéza   genetika   MeSH
• nádory genetika   metabolismus   MeSH
• nestabilita genomu * MeSH
• polyadenylace MeSH
• poškození DNA * MeSH
• prekurzory RNA biosyntéza   genetika   MeSH
• proteiny buněčného cyklu genetika   metabolismus   MeSH
• proteiny vázající RNA MeSH
• regulace genové exprese u nádorů MeSH
• replikace DNA * MeSH
• RNA nádorová biosyntéza   genetika   MeSH
• štěpení RNA * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA nádorová MeSH
• DNA vazebné proteiny MeSH
• heteroduplexy nukleové kyseliny MeSH
• jaderné proteiny MeSH
• messenger RNA MeSH
• prekurzory RNA MeSH
• proteiny buněčného cyklu MeSH
• proteiny vázající RNA MeSH
• RNA nádorová MeSH
• THOC1 protein, human MeSH Prohlížeč
• WDR33 protein, human MeSH Prohlížeč

Current anti-cancer strategy takes advantage of tumour specific abnormalities in DNA damage response to radio- or chemo-therapy. Inhibition of the ATR/Chk1 pathway has been shown to be synthetically lethal in cells with high levels of oncogene-induced replication stress and in p53- or ATM- deficient cells. In the presented study, we aimed to elucidate molecular mechanisms underlying radiosensitization of T-lymphocyte leukemic MOLT-4 cells by VE-821, a higly potent and specific inhibitor of ATR. We combined multiple approaches: cell biology techniques to reveal the inhibitor-induced phenotypes, and quantitative proteomics, phosphoproteomics, and metabolomics to comprehensively describe drug-induced changes in irradiated cells. VE-821 radiosensitized MOLT-4 cells, and furthermore 10 μM VE-821 significantly affected proliferation of sham-irradiated MOLT-4 cells. We detected 623 differentially regulated phosphorylation sites. We revealed changes not only in DDR-related pathways and kinases, but also in pathways and kinases involved in maintaining cellular metabolism. Notably, we found downregulation of mTOR, the main regulator of cellular metabolism, which was most likely caused by an off-target effect of the inhibitor, and we propose that mTOR inhibition could be one of the factors contributing to the phenotype observed after treating MOLT-4 cells with 10 μM VE-821. In the metabolomic analysis, 206 intermediary metabolites were detected. The data indicated that VE-821 potentiated metabolic disruption induced by irradiation and affected the response to irradiation-induced oxidative stress. Upon irradiation, recovery of damaged deoxynucleotides might be affected by VE-821, hampering DNA repair by their deficiency. Taken together, this is the first study describing a complex scenario of cellular events that might be ATR-dependent or triggered by ATR inhibition in irradiated MOLT-4 cells. Data are available via ProteomeXchange with identifier PXD008925.

• MeSH
• aminokyselinové motivy MeSH
• ATM protein antagonisté a inhibitory   MeSH
• biologické markery MeSH
• fosfoproteiny * chemie   metabolismus   MeSH
• fosforylace MeSH
• genová ontologie MeSH
• inhibitory proteinkinas farmakologie   MeSH
• kontrolní body buněčného cyklu účinky léků   účinky záření   MeSH
• lidé MeSH
• metabolom * MeSH
• metabolomika metody   MeSH
• nádorové buněčné linie MeSH
• proteom * MeSH
• proteomika metody   MeSH
• pyraziny farmakologie   MeSH
• radiosenzibilizující látky farmakologie   MeSH
• signální transdukce MeSH
• sulfony farmakologie   MeSH
• tolerance záření účinky léků   MeSH
• TOR serin-threoninkinasy metabolismus   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• výpočetní biologie metody   MeSH
• záření gama MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide MeSH Prohlížeč
• ATM protein MeSH
• ATR protein, human MeSH Prohlížeč
• biologické markery MeSH
• fosfoproteiny * MeSH
• inhibitory proteinkinas MeSH
• MTOR protein, human MeSH Prohlížeč
• proteom * MeSH
• pyraziny MeSH
• radiosenzibilizující látky MeSH
• sulfony MeSH
• TOR serin-threoninkinasy MeSH