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Project description:Inhibitors of the mitotic kinesin Kif11 are anti-mitotics that, unlike vinca alkaloids or taxanes, do not disrupt microtubules and are not neurotoxic. However, development of resistance has limited their clinical utility. While resistance to Kif11 inhibitors in other cell types is due to mechanisms that prevent these drugs from disrupting mitosis, we find that in glioblastoma (GBM), resistance to the Kif11 inhibitor ispinesib works instead through suppression of apoptosis driven by activation of STAT3. This form of resistance requires dual phosphorylation of STAT3 residues Y705 and S727, mediated by SRC and epidermal growth factor receptor (EGFR), respectively. Simultaneously inhibiting SRC and EGFR reverses this resistance, and combined targeting of these two kinases in vivo with clinically available inhibitors is synergistic and significantly prolongs survival in ispinesib-treated GBM-bearing mice. We thus identify a translationally actionable approach to overcoming Kif11 inhibitor resistance that may work to block STAT3-driven resistance against other anti-cancer therapies as well.
| S-EPMC10018805 | biostudies-literature
Project description:The outcome for patients afflicted with glioblastoma (GBM), the most common and malignant of primary brain tumors in adults, has changed little despite decades of clinical, translational, and basic research. Any effective, systemically administered GBM therapy needs to target cellular components that are indispensable for the malignant phenotype with drugs that cross the blood brain barrier (BBB) and have manageable toxicities. However, while a number of signaling pathways have been shown to drive the malignant phenotype in GBM, and while relatively non-toxic, CNS permeant inhibitors of several of these have been identified, their efficacy in GBM has been disappointing. In this study, we examine the mechanism of resistance to the Kif11 inhibitor ispinesib in murine and human GBM. We find that development of resistance in these tumors occurs by a mechanism not previously described for Kif11 inhibitors, is associated with broad scale transcriptomic and phenotypic changes, and can be reversed with drugs that are FDA approved or in clinical investigation. Our findings also point to ways of enhancing the efficacy of Kif11 inhibitors that are directly translatable into a clinical setting.The outcome for patients afflicted with glioblastoma (GBM), the most common and malignant of primary brain tumors in adults, has changed little despite decades of clinical, translational, and basic research. Any effective, systemically administered GBM therapy needs to target cellular components that are indispensable for the malignant phenotype with drugs that cross the blood brain barrier (BBB) and have manageable toxicities. However, while a number of signaling pathways have been shown to drive the malignant phenotype in GBM, and while relatively non-toxic, CNS permeant inhibitors of several of these have been identified, their efficacy in GBM has been disappointing. In this study, we examine the mechanism of resistance to the Kif11 inhibitor ispinesib in murine and human GBM. We find that development of resistance in these tumors occurs by a mechanism not previously described for Kif11 inhibitors, is associated with broad scale transcriptomic and phenotypic changes, and can be reversed with drugs that are FDA approved or in clinical investigation. Our findings also point to ways of enhancing the efficacy of Kif11 inhibitors that are directly translatable into a clinical setting.
2023-05-10 | PXD030715 | Pride
Project description:Inhibitors of the mitotic kinesin Kif11 are anti-mitotics that, unlike vinca alkaloids or taxanes, do not disrupt microtubules and are not neurotoxic. However, development of resistance has limited their clinical utility. While resistance to Kif11 inhibitors in other cell types is due to mechanisms that prevent these drugs from disrupting mitosis, we find that in glioblastoma (GBM), resistance to the Kif11 inhibitor ispinesib works instead through suppression of apoptosis driven by activation of STAT3. This form of resistance requires dual phosphorylation of STAT3 residues Y705 and S727, mediated by SRC and EGFR, respectively. Simultaneously inhibiting SRC and EGFR reverses this resistance, and combined targeting of these two kinases in vivo with clinically available inhibitors is synergistic and significantly prolongs survival in ispinesib-treated GBM-bearing mice. We thus identify a translationally actionable approach to overcoming Kif11 inhibitor resistance that may work to block STAT3-driven resistance against other anti-cancer therapies as well.
2022-01-09 | GSE193179 | GEO
Project description:Inhibitors of the mitotic kinesin Kif11 are anti-mitotics that, unlike vinca alkaloids or taxanes, do not disrupt microtubules and are not neurotoxic. However, development of resistance has limited their clinical utility. While resistance to Kif11 inhibitors in other cell types is due to mechanisms that prevent these drugs from disrupting mitosis, we find that in glioblastoma (GBM), resistance to the Kif11 inhibitor ispinesib works instead through suppression of apoptosis driven by activation of STAT3. This form of resistance requires dual phosphorylation of STAT3 residues Y705 and S727, mediated by SRC and EGFR, respectively. Simultaneously inhibiting SRC and EGFR reverses this resistance, and combined targeting of these two kinases in vivo with clinically available inhibitors is synergistic and significantly prolongs survival in ispinesib-treated GBM-bearing mice. We thus identify a translationally actionable approach to overcoming Kif11 inhibitor resistance that may work to block STAT3-driven resistance against other anti-cancer therapies as well.
2022-01-09 | GSE193178 | GEO
Project description:Activation of STAT3 through SRC and EGFR Drives Resistance to a Mitotic Kinesin Inhibitor in Glioblastoma
| PRJNA795186 | ENA
Project description:Activation of STAT3 through SRC and EGFR Drives Resistance to a Mitotic Kinesin Inhibitor in Glioblastoma [scRNA-seq]
| PRJNA795188 | ENA
Project description:Activation of STAT3 through SRC and EGFR Drives Resistance to a Mitotic Kinesin Inhibitor in Glioblastoma [bulk RNA-seq]
| PRJNA795189 | ENA
Project description:BackgroundPatients with metastatic bladder cancer have very poor prognosis and predictive biomarkers are urgently needed for early clinical detection and intervention. In this study, we evaluate the effect and mechanism of Suprabasin (SBSN) on bladder cancer metastasis.MethodsA tissue array was used to detect SBSN expression by immunohistochemistry. A tumour-bearing mouse model was used for metastasis evaluation in vivo. Transwell and wound-healing assays were used for in vitro evaluation of migration and invasion. Comprehensive molecular screening was achieved by western blotting, immunofluorescence, luciferase reporter assay, and ELISA.ResultsSBSN was found markedly overexpressed in bladder cancer, and indicated poor prognosis of patients. SBSN promoted invasion and metastasis of bladder cancer cells both in vivo and in vitro. The secreted SBSN exhibited identical biological function and regulation in bladder cancer metastasis, and the interaction of secreted SBSN and EGFR could play an essential role in activating the signalling in which SBSN enhanced the phosphorylation of EGFR and SRC kinase, followed with phosphorylation and nuclear location of STAT3.ConclusionsOur findings highlight that SBSN, and secreted SBSN, promote bladder cancer metastasis through activation of EGFR/SRC/STAT3 pathway and identify SBSN as a potential diagnostic and therapeutic target for bladder cancer.
| S-EPMC9296541 | biostudies-literature
Project description:Non-small-cell lung cancer patients with activating epidermal growth factor receptor (EGFR) mutations typically benefit from ?EGFR tyrosine kinase inhibitor treatment. However, virtually all patients succumb to acquired EGFR tyrosine kinase inhibitor resistance that occurs via diverse mechanisms. The diversity and unpredictability of EGFR tyrosine kinase inhibitor resistance mechanisms presents a challenge for developing new treatments to overcome EGFR tyrosine kinase inhibitor resistance. Here, we show that Akt activation is a convergent feature of acquired EGFR tyrosine kinase inhibitor resistance, across a spectrum of diverse, established upstream resistance mechanisms. Combined treatment with an EGFR tyrosine kinase inhibitor and Akt inhibitor causes apoptosis and synergistic growth inhibition in multiple EGFR tyrosine kinase inhibitor-resistant non-small-cell lung cancer models. Moreover, phospho-Akt levels are increased in most clinical specimens obtained from EGFR-mutant non-small-cell lung cancer patients with acquired EGFR tyrosine kinase inhibitor resistance. Our findings provide a rationale for clinical trials testing Akt and EGFR inhibitor co-treatment in patients with elevated phospho-Akt levels to therapeutically combat the heterogeneity of EGFR tyrosine kinase inhibitor resistance mechanisms.EGFR-mutant non-small cell lung cancer are often resistant to EGFR tyrosine kinase inhibitor treatment. In this study, the authors show that resistant tumors display high Akt activation and that a combined treatment with AKT inhibitors causes synergistic tumour growth inhibition in vitro and in vivo.
| S-EPMC5583255 | biostudies-literature
Project description:PURPOSE:EGF receptor (EGFR) is upregulated in most epithelial cancers where signaling through EGFR contributes to cancer cell proliferation and survival. The limited clinical efficacy of EGFR inhibitors suggests that identification of resistance mechanisms may identify new pathways for therapeutic targeting. STAT3 is upregulated in many cancers and activated via both EGFR-dependent and -independent pathways. In the present study, we tested the consequences of STAT3 inhibition in EGFR inhibitor-resistant head and neck squamous cell carcinoma (HNSCC) and bladder cancer models to determine whether STAT3 blockade can enhance responses to EGFR targeting. EXPERIMENTAL DESIGN:pSTAT3 expression was assessed in human HNSCC tumors that recurred following cetuximab treatment. Cetuximab-sensitive and -resistant cell lines were treated with a STAT3 decoy to determine EC(50) concentrations and the effects on STAT3 target gene expression by Western blotting. In vivo assays included evaluation of antitumor efficacy of STAT3 decoy in cetuximab-sensitive and -resistant models followed by immunoblotting for STAT3 target protein expression. RESULTS:Targeting STAT3 with a STAT3 decoy reduced cellular viability and the expression of STAT3 target genes in EGFR inhibitor resistance models. The addition of a STAT3 inhibitor to EGFR blocking strategies significantly enhanced antitumor effects in vivo. Biopsies from HNSCC tumors that recurred following cetuximab treatment showed increased STAT3 activation compared with pretreatment biopsies. CONCLUSIONS:These results suggest that STAT3 activation contributes to EGFR inhibitor resistance both in HNSCC and bladder cancer where concomitant targeting of STAT3 may represent an effective treatment strategy.
| S-EPMC3445706 | biostudies-literature