CDK4/6 inhibition stabilizes disease in patients with p16-null non-small cell lung cancer and is synergistic with mTOR inhibition.
Ontology highlight
ABSTRACT:
SUBMITTER: Gopalan PK
PROVIDER: S-EPMC6324768 | biostudies-literature | 2018 Dec
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:PurposeIntrahepatic cholangiocarcinoma (ICC) is an aggressive cancer type, lacking effective therapies and associated with a dismal prognosis. Palbociclib is a selective CDK4/6 inhibitor, which has been shown to suppress cell proliferation in many experimental cancer models. Recently, we demonstrated that pan-mTOR inhibitors, such as MLN0128, effectively induce apoptosis, although have limited efficacy in restraining proliferation of ICC cells. Here, we tested the hypothesis that palbociclib, due to its antproliferative properties in many cancer types, might synergize with MLN0128 to impair ICC growth.Experimental designHuman ICC cell lines and the AKT/YapS127A ICC mouse model were used to test the therapeutic efficacy of palbociclib and MLN0128, either alone or in combination.ResultsAdministration of palbociclib suppressed in vitro ICC cell growth by inhibiting cell-cycle progression. Concomitant administration of palbociclib and MLN0128 led to a pronounced, synergistic growth constraint of ICC cell lines. Furthermore, while treatment with palbociclib or MLN0128 alone resulted in tumor growth reduction in AKT/YapS127A mice, a remarkable tumor regression was achieved when the two drugs were administered simultaneously. Mechanistically, palbociclib was found to potentiate MLN0128 mTOR inhibition activity, whereas MLN0128 prevented the upregulation of cyclin D1 induced by palbociclib treatment.ConclusionsOur study indicates the synergistic activity of palbociclib and MLN0128 in inhibiting ICC cell proliferation. Thus, combination of CDK4/6 and mTOR inhibitors might represent a novel, promising, and effective therapeutic approach against human ICC.See related commentary by Malumbres, p. 6.
| S-EPMC6423983 | biostudies-literature
Project description:Purpose: Glioblastoma (GBM) is a deadly brain tumor marked by dysregulated signaling and aberrant cell-cycle control. Molecular analyses have identified that the CDK4/6-Rb-E2F axis is dysregulated in about 80% of GBMs. Single-agent CDK4/6 inhibitors have failed to provide durable responses in GBM, suggesting a need to combine them with other agents. We investigate the efficacy of the combination of CDK4/6 inhibition and mTOR inhibition against GBM.Experimental Design: Preclinical in vitro and in vivo assays using primary GBM cell lines were performed.Results: We show that the CDK4/6 inhibitor palbociclib suppresses the activity of downstream mediators of the mTOR pathway, leading to rebound mTOR activation that can be blocked by the mTOR inhibitor everolimus. We further show that mTOR inhibition with everolimus leads to activation of the Ras mediator Erk that is reversible with palbociclib. The combined treatment strongly disrupts GBM metabolism, resulting in significant apoptosis. Further increasing the utility of the combination for brain cancers, everolimus significantly increases the brain concentration of palbociclib.Conclusions: Our findings demonstrate that the combination of CDK4/6 and mTOR inhibition has therapeutic potential against GBM and suggest it should be evaluated in a clinical trial. Clin Cancer Res; 23(22); 6958-68. ©2017 AACR.
| S-EPMC5690820 | biostudies-literature
Project description:Tumor suppressor SMARCA4 (BRG1), a key SWI/SNF chromatin remodeling gene, is frequently inactivated in cancers and is not directly druggable. We recently uncovered that SMARCA4 loss in an ovarian cancer subtype causes cyclin D1 deficiency leading to susceptibility to CDK4/6 inhibition. Here, we show that this vulnerability is conserved in non-small cell lung cancer (NSCLC), where SMARCA4 loss also results in reduced cyclin D1 expression and selective sensitivity to CDK4/6 inhibitors. In addition, SMARCA2, another SWI/SNF subunit lost in a subset of NSCLCs, also regulates cyclin D1 and drug response when SMARCA4 is absent. Mechanistically, SMARCA4/2 loss reduces cyclin D1 expression by a combination of restricting CCND1 chromatin accessibility and suppressing c-Jun, a transcription activator of CCND1. Furthermore, SMARCA4 loss is synthetic lethal with CDK4/6 inhibition both in vitro and in vivo, suggesting that FDA-approved CDK4/6 inhibitors could be effective to treat this significant subgroup of NSCLCs.
| S-EPMC6362083 | biostudies-literature
Project description:ObjectiveActivating KRAS mutations are the most common drivers in the development of non-small cell lung cancer (NSCLC). However, unsuccess of treatment by direct inhibition of KRAS has been proven. Deregulation of PI3K signaling plays an important role in tumorigenesis and drug resistance in NSCLC. The activity of PI3Kα-selective inhibition against KRAS-mutated NSCLC remains largely unknown.MethodsCell proliferation was detected by sulforhodamine B assay. Cell cycle distribution and apoptosis were measured by flow cytometry. Cell signaling was assessed by Western blot and immunohistochemistry. RNA interference was used to down-regulate the expression of cyclin D1. Human NSCLC xenografts were employed to detect therapeutic efficacy in vivo.ResultsCYH33 possessed variable activity against a panel of KRAS-mutated NSCLC cell lines. Although CYH33 blocked AKT phosphorylation in all tested cells, Rb phosphorylation decreased in CYH33-sensitive, but not in CYH33-resistant cells, which was consistent with G1 phase arrest in sensitive cells. Combined treatment with the CDK4/6 inhibitor, PD0332991, and CYH33 displayed synergistic activity against the proliferation of both CYH33-sensitive and CYH33-resistant cells, which was accompanied by enhanced G1-phase arrest. Moreover, down-regulation of cyclin D1 sensitized NSCLC cells to CYH33. Reciprocally, CYH33 abrogated the PD0332991-induced up-regulation of cyclin D1 and phosphorylation of AKT in A549 cells. Co-treatment with these two drugs demonstrated synergistic activity against A549 and H23 xenografts, with enhanced inhibition of Rb phosphorylation.ConclusionsSimultaneous inhibition of PI3Kα and CDK4/6 displayed synergistic activity against KRAS-mutated NSCLC. These data provide a mechanistic rationale for the combination of a PI3Kα inhibitor and a CDK4/6 inhibitor for the treatment of KRAS-mutated NSCLC.
| S-EPMC6528459 | biostudies-literature
Project description:Cancer metabolism has greatly interested researchers. Mammalian target of rapamycin (mTOR) is dysregulated in a variety of cancers and considered to be an appealing therapeutic target. It has been proven that growth factor signal, mediated by mTOR complex 1 (mTORC1), drives cancer metabolism by regulating key enzymes in metabolic pathways. However, the role of mTORC2 in cancer metabolism has not been thoroughly investigated. In this study, by employing automated spectrophotometry, we found the level of glucose uptake was decreased in non-small-cell lung carcinoma (NSCLC) A549, PC-9 and SK-MES-1 cells treated with rapamycin or siRNA against Raptor, indicating that the inhibition of mTORC1 attenuated glycolytic metabolism in NSCLC cells. Moreover, the inhibition of AKT reduced glucose uptake in the cells as well, suggesting the involvement of AKT pathway in mTORC1 mediated glycolytic metabolism. Furthermore, our results showed a significant decrease in glucose uptake in rictor down-regulated NSCLC cells, implying a critical role of mTORC2 in NSCLC cell glycolysis. In addition, the experiments for MTT, ATP, and clonogenic assays demonstrated a reduction in cell proliferation, cell viability, and colony forming ability in mTOR inhibiting NSCLC cells. Interestingly, the combined application of mTORC1/2 inhibitors and glycolysis inhibitor not only suppressed the cell proliferation and colony formation, but also induced cell apoptosis, and such an effect of the combined application was stronger than that caused by mTORC1/2 inhibitors alone. In conclusion, this study reports a novel effect of mTORC2 on NSCLC cell metabolism, and reveals the synergistic effects between mTOR complex 1/2 and glycolysis inhibitors, suggesting that the combined application of mTORC1/2 and glycolysis inhibitors may be a new promising approach to treat NSCLC.
| S-EPMC4503566 | biostudies-literature
Project description:Increasing evidence has confirmed that deubiquitinating enzymes play an important role in lung cancer progression. In the current study, we investigated the expression profile of deubiquitinating enzymes in non-small cell lung cancer (NSCLC) tissues and identified OTUB2 as an upregulated deubiquitinating enzyme. The role of OTUB2 in NSCLC is unknown. Methods: Quantitative, real-time PCR and Western blot were used to detect OTUB2 and U2AF2 expression in NSCLC tissues. The correlations between OTUB2 and U2AF2 expression and clinicopathologic features were then analyzed. We used In vitro Cell Counting Kit-8 (CCK-8) , colony formation , and trans-well invasion assays to investigate the function of OTUB2 and U2AF2 in tumorigenesis. The regulation of glycolysis by OTUB2 and U2AF2 was assessed by determining the extracellular acid ratio, glucose consumption, and lactate production. The mechanism of OTUB2 was explored through co-immunoprecipitation and mass spectrometry analyses. A xenograft model was also used to study the tumorigenesis role of OTUB2 In vivo. Results: OTUB2 expression was significantly upregulated in primary NSCLC tissues and greatly associated with metastasis, advanced tumor stages, poor survival, and recurrence. In NSCLC cell lines, OTUB2 promoted cell growth, colony formation, migration, and invasive activities. Mechanistic investigations showed that OTUB2 stimulated the Warburg effect and induced the activation of the serine/threonine kinase/mechanistic target of rapamycin kinase (AKT/mTOR) pathway in different NSCLC cells. More importantly, OTUB2 promoted NSCLC progression, which was largely dependent on the direct binding to and deubiquitination of U2AF2, at least in NSCLC cells. U2AF2 expression was also significantly upregulated in primary NSCLC tissues and dramatically associated with metastasis, advanced tumor stages, poor survival, and recurrence. Importantly, a positive correlation between the protein expression of OTUB2 and U2AF2 in NSCLC tissues was found. In vivo experiments indicated that OTUB2 promoted xenograft tumor growth of NSCLC cell. In addition, our results suggest that high expression of OTUB2, U2AF2 and PGK1 is significantly associated with worse prognosis in NSCLC patients. Conclusion: Taken together, the present study provides the first evidence that OTUB2 acts as a pivotal driver in NSCLC tumorigenesis by stabilizing U2AF2 and activating the AKT/mTOR pathway and the Warburg effect. It may serve as a new potential prognostic indicator and therapeutic target in NSCLC.
| S-EPMC6332791 | biostudies-literature
Project description:Lung cancer is the leading cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC) accounts for 80%-85% of lung cancer. Malignant tumors can proliferate indefinitely, and cell cycle regulation is abnormal which is one of the characteristics of malignant tumor. Cyclin D-dependent kinase (CDK) 4/6 inhibitor can prevent tumor cells from entering S phase through G? phase and inhibit tumor proliferation. The CDK4/6 inhibitor has achieved good effect in hormone receptor positive breast cancer, and CDK4/6 inhibitor combined with endocrine therapy has become a standard treatment for this kind of patients. Cell cycle regulation is usually abnormal in NSCLC, which incidence is about 22%-45%. CDK4/6 inhibitors have also carried out a series of research and achieved some results, which may become a new treatment in the future. This review focuses on the research progress of CDK4/6 inhibitors in NSCLC, including the mechanism and the approved drugs, clinical research progress in NSCLC, biomarkers for efficacy prediction and current limitations.
| S-EPMC7118338 | biostudies-literature
Project description:Epidermal growth factor receptor (EGFR) is overexpressed in lung cancer patients. Despite treatment with various EGFR tyrosine kinase inhibitors, recurrence and metastasis of lung cancer are inevitable. Docetaxel (DTX) is an effective conventional drug that is used to treat various cancers. Several researchers have studied the use of traditional herbal medicine in combination with docetaxel, to improve lung cancer treatment. SH003, a novel herbal mixture, exerts anticancer effects in different cancer cell types. Here, we aimed to investigate the apoptotic and anticancer effects of SH003 in combination with DTX, in human non-small-cell lung cancer (NSCLC). SH003, with DTX, induced apoptotic cell death, with increased expression of cleaved caspases and cleaved poly (ADP-ribose) polymerase in NSCLC cells. Moreover, SH003 and DTX induced the apoptosis of H460 cells via the suppression of the EGFR and signal transducer and activator of transcription 3 (STAT3) signaling pathways. In H460 tumor xenograft models, the administration of SH003 or docetaxel alone diminished tumor growth, and their combination effectively killed cancer cells, with increased expression of apoptotic markers and decreased expression of p-EGFR and p-STAT3. Collectively, the combination of SH003 and DTX may be a novel anticancer strategy to overcome the challenges that are associated with conventional lung cancer therapy.
| S-EPMC8395077 | biostudies-literature
Project description:Malignant pleural mesothelioma (MPM) is a progressive malignancy associated to the exposure of asbestos fibers. The most frequently inactivated tumor suppressor gene in MPM is CDKN2A/ARF, encoding for the cell cycle inhibitors p16INK4a and p14ARF, deleted in about 70% of MPM cases. Considering the high frequency of alterations of this gene, we tested in MPM cells the efficacy of palbociclib (PD-0332991), a highly selective inhibitor of cyclin-dependent kinase (CDK) 4/6. The analyses were performed on a panel of MPM cell lines and on two primary culture cells from pleural effusion of patients with MPM. All the MPM cell lines, as well as the primary cultures, were sensitive to palbociclib with a significant blockade in G0/G1 phase of the cell cycle and with the acquisition of a senescent phenotype. Palbociclib reduced the phosphorylation levels of CDK6 and Rb, the expression of myc with a concomitant increased phosphorylation of AKT. Based on these results, we tested the efficacy of the combination of palbociclib with the PI3K inhibitors NVP-BEZ235 or NVP-BYL719. After palbociclib treatment, the sequential association with PI3K inhibitors synergistically hampered cell proliferation and strongly increased the percentage of senescent cells. In addition, AKT activation was repressed while p53 and p21 were up-regulated. Interestingly, two cycles of sequential drug administration produced irreversible growth arrest and senescent phenotype that were maintained even after drug withdrawal. These findings suggest that the sequential association of palbociclib with PI3K inhibitors may represent a valuable therapeutic option for the treatment of MPM.
| S-EPMC5508477 | biostudies-literature
Project description:PurposePD-0332991 is a selective inhibitor of the CDK4/6 kinases with the ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range. Here we investigate the role of CDK4/6 inhibition in human ovarian cancer.Experimental designWe examined the effects of PD-0332991 on proliferation, cell-cycle, apoptosis, and Rb phosphorylation using a panel of 40 established human ovarian cancer cell lines. Molecular markers for response prediction, including p16 and Rb, were studied using gene expression profiling, Western blot, and array CGH. Multiple drug effect analysis was used to study interactions with chemotherapeutic drugs. Expression of p16 and Rb was studied using immunohistochemistry in a large clinical cohort of ovarian cancer patients.ResultsConcentration-dependent antiproliferative effects of PD-0332991 were seen in all ovarian cancer cell lines, but varied significantly between individual lines. Rb-proficient cell lines with low p16 expression were most responsive to CDK4/6 inhibition. Copy number variations of CDKN2A, RB, CCNE1, and CCND1 were associated with response to PD-0332991. CDK4/6 inhibition induced G0/G1 cell cycle arrest, blocked Rb phosphorylation in a concentration-and time-dependent manner, and enhanced the effects of chemotherapy. Rb-proficiency with low p16 expression was seen in 97/262 (37%) of ovarian cancer patients and was independently associated with poor progression-free survival (adjusted relative risk 1.49, 95% CI 1.00-2.24, P = 0.052).ConclusionsPD-0332991 shows promising biologic activity in ovarian cancer cell lines. Assessment of Rb and p16 expression may help select patients most likely to benefit from CDK4/6 inhibition in ovarian cancer.
| S-EPMC4598646 | biostudies-literature