ABSTRACT: Resistance to Palbociclib involves multiple mechanisms amenable to targeting with drug holidays or drug switching to improve therapeutic outcome [Illumina]
Project description:Resistance to Palbociclib involves multiple mechanisms amenable to targeting with drug holidays or drug switching to improve therapeutic outcome
Project description:Resistance to Palbociclib involves multiple mechanisms amenable to targeting with drug holidays or drug switching to improve therapeutic outcome [Affymetrix]
Project description:Ovarian cancer (OC) is the most lethal gynecological carcinoma because of the lack of early diagnostic markers and effective drug targets. Discovery of new therapeutic targets in OC to improve the treatment outcome is urgently needed. Patients with recurrent EOC after initial therapy have few treatment options that greatly compromises their quality of life and life expectancy. Discovery of new therapeutic targets in EOC to improve the treatment outcome is urgently needed. Proteomic analysis is one of the approaches to identify therapeutic targets in OC.
Project description:Resistance to chemotherapy is one of the main causes of mortality in late-stage nasopharyngeal carcinoma (NPC) with dismal prognosis and limited therapeutic options. Therefore, there is an urgent need to exploit new therapeutic targets to improve current clinical outcome. In this study, we identified pacritinib, a late stage clinical drug targeting IRAK1, as a sensitizer to resistance of paclitaxel in NPC. Through analysis of both chemoresistant cellular models and clinical samples of relapse and metastasis, we have shown that aberrant IRAK1-S100A9 deregulation is correlated with chemoresistance and prognosticates poor clinical outcome. Further functional studies demonstrated that genetic and pharmacological inhibition of IRAK1-S100A9 axis overcomes the resistance to paclitaxel and combination of pacritinib with paclitaxel exhibited superior anti-tumor effect in both in vivo and in vitro models.
Project description:Palbociclib (Ibrance, Pfizer) is a recent drug approved by the FDA for phase 3 clinical trials in treating estrogen-receptor-positive and HER2-negative breast cancer. In vitro, palbociclib, a selective inhibitor of CDK4 and CDK6, was shown to reduce cellular proliferation of breast cancer cell lines by blocking progression of cells from G1 into S phase of the cell cycle. While the primary targets of palbociclib have been deciphered, the molecular mechanisms leading to drug resistance as well as off-targets effects of palbociclib are not known. To identify new palbociclib targets we propose a quantitative mass spectrometry and a Cellular Thermal Shift Assay (CETSA) that works under the assumption that protein-drug interaction stabilises the protein thus, leading to an increase in thermostability
Project description:Cyclin-dependent kinases 4 and 6 (CDK4/6) are essential drivers of the cell cycle and are also critical for the initiation and progression of diverse malignancies. Pharmacological inhibitors targeting CDK4/6 have demonstrated significant activity against various tumor types such as breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i) (such as palbociclib) remains an immense obstacle in clinical and the underlying mechanisms have not been fully understood. Using quantitative high-throughput combinational screen (qHTCS) and genomic sequencing, we report that the Microphthalmia-associated transcription factor (MITF), was significantly elevated in palbociclib-resistance cells. Inhibition of MITF can enhance the therapeutic efficacy of Palbociclib and surmount Palbociclib resistance both in vitro and in vivo. Mechanistically, we found that O-GlcNAc transferase (OGT) modifies MITF with O-GlcNAcylation at Serine 49 (Ser49) within its nuclear localization signal (NLS), thereby promoting MITF binding to importin α/ β and facilitating its nuclear transportation, which is crucial in regulating senescence. Significantly, clinical studies also confirm that MITF was elevated in palbociclib-resistance patients. Collectively, these results reveal a previously unrecognized mechanism by which MITF-mediated palbociclib resistance, and provide valuable insights for the development of innovative therapeutic strategies in future clinical contexts.
Project description:Cyclin-dependent kinases 4 and 6 (CDK4/6) are essential drivers of the cell cycle and are also critical for the initiation and progression of diverse malignancies. Pharmacological inhibitors targeting CDK4/6 have demonstrated significant activity against various tumor types such as breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i) (such as palbociclib) remains an immense obstacle in clinical and the underlying mechanisms have not been fully understood. Using quantitative high-throughput combinational screen (qHTCS) and genomic sequencing, we report that the Microphthalmia-associated transcription factor (MITF), was significantly elevated in palbociclib-resistance cells. Inhibition of MITF can enhance the therapeutic efficacy of Palbociclib and surmount Palbociclib resistance both in vitro and in vivo. Mechanistically, we found that O-GlcNAc transferase (OGT) modifies MITF with O-GlcNAcylation at Serine 49 (Ser49) within its nuclear localization signal (NLS), thereby promoting MITF binding to importin α/ β and facilitating its nuclear transportation, which is crucial in regulating senescence. Significantly, clinical studies also confirm that MITF was elevated in palbociclib-resistance patients. Collectively, these results reveal a previously unrecognized mechanism by which MITF-mediated palbociclib resistance, and provide valuable insights for the development of innovative therapeutic strategies in future clinical contexts.
Project description:Chemoresistance largely hampers the clinical use of chemo drugs for cancer patients, combination or sequential drug treatment regimens have been designed to minimize chemotoxic and resensitize chemoresistance. In this work, the cytotoxic effect of cisplatin was found to be enhanced by palbociclib pretreatment. With the integration of proteomic and N-glycoproteomic workflow, we found that palbociclib alone mainly enhances the N-glycosylation alterations in Hela cells, while cisplatin majorly increases the DEPs (different expression proteins) including apoptosis proteins. As a result, the sequential use of two drugs induced a higher expression level of apoptosis proteins BAX and BAK. Those altered n-glycoproteins induced by palbociclib were implicated in pathways that are closely associated with cell membrane modification and drug sensitivity. Specifically, the top 4 frequently glycosylated proteins FOLR1, L1CAM, CD53, and LAMP1 were all drug resistance or drug sensitivity associated proteins located mainly in the cell membrane. It is suspected that palbociclib-induced N-glycosylation on the membrane protein allowed the Hela cell to become more vulnerable to cisplatin. Our study provided new insights into the mechanism underlying the sequential use of target drug and chemotherapy drug, meanwhile suggesting a high-efficiency approach that involves proteomic and N-glycoproteomic to facilitate drug understanding.
