Microtubule Engagement with Taxane Is Altered in Taxane-Resistant Gastric Cancer

Galletti, Giuseppe; Zhang, Chao; Gjyrezi, Ada; Cleveland, Kyle; Zhang, Jiaren; Powell, S. E.; Thakkar, Prashant V.; Betel, Doron; Shah, Manish A.; Giannakakou, Paraskevi

doi:10.1158/1078-0432.ccr-19-3018

Cited by 24 publications

(14 citation statements)

References 52 publications

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“…Mechanisms of resistance to cytotoxic therapy are multifactorial and are likely to include both tumor-intrinsic genomic alterations and aspects of the tumor microenvironment. We have previously demonstrated that microtubule engagement within the tumor is an important prerequisite for taxane efficacy (27). Here, our data suggest that both HER2 amplification/overexpression and enrichment of M2 macrophages in the tumor immune microenvironment may also play a role in taxane sensitivity.…”

Section: Cabazitaxel In Gastricsupporting

confidence: 54%

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Multicenter Phase II Study of Cabazitaxel in Advanced Gastroesophageal Cancer: Association of HER2 Expression and M2-Like Tumor-Associated Macrophages with Patient Outcome

Shah

Enzinger

et al. 2020

Clinical Cancer Research

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We examined cabazitaxel, a novel next-generation taxoid, in patients with metastatic gastric cancer in a multicenter phase II study.Patients and Methods: Patients who have progressed on one or more prior therapies for locally advanced, unresectable, or metastatic disease were eligible, and prior taxane therapy was allowed. Taxane-na€ ve and pretreated cohorts were analyzed independently for efficacy. The primary endpoint for both cohorts was progression-free survival (PFS) using RECIST 1.1, using a Simon's twostage design (10% significance and 80% power) for both cohorts. Comprehensive molecular annotation included whole exome and bulk RNA sequencing.Results: Fifty-three patients enrolled in the taxane-na€ ve cohort (Arm A) and 23 patients in the prior-taxane cohort (Arm B), from January 8, 2013, to April 8, 2015: median age 61.7 years (range, 35.5-91.8 years), 66% male, 66% Caucasian. The most common adverse events included neutropenia (17% Arm A and 39% Arm B), fatigue/muscle weakness (13%), and hematuria (12%). In Arm A, the 3-month PFS rate was 28% [95% confidence interval (CI), 17%-42%] and did not meet the prespecified efficacy target. The 3-month PFS rate in Arm B was 35% (95% CI, 16%-57%) and surpassed its efficacy target. HER2 amplification or overexpression was associated with improved disease control (P ¼ 0.003), PFS (P ¼ 0.04), and overall survival (P ¼ 0.002). An M2 macrophage signature was also associated with improved survival (P ¼ 0.031).Conclusions: Cabazitaxel has modest activity in advanced gastric cancer, including in patients previously treated with taxanes. Her2 amplification/overexpression and M2 high macrophage signature are potential biomarkers for taxane efficacy that warrant further evaluation.

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Section: Cabazitaxel In Gastricsupporting

confidence: 54%

“…We have previously demonstrated that microtubule bundling identified on on-treatment biopsies is associated with response to therapy (27). The underlying purpose of the correlative studies in this report was to identify any potential association of genetic aberrations or tumor microenvironment signatures with cabazitaxel activity.…”

Section: Correlative Studiesmentioning

confidence: 89%

Multicenter Phase II Study of Cabazitaxel in Advanced Gastroesophageal Cancer: Association of HER2 Expression and M2-Like Tumor-Associated Macrophages with Patient Outcome

Shah

Enzinger

et al. 2020

Clinical Cancer Research

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“…Several studies have debated the possible correlation between taxane resistance and high ßIII-tubulin expression. Expression of the neuron-specific βIII-tubulin isotype correlated with taxane resistance in vitro and in vivo and has been extensively studied as a clinical biomarker of taxane efficacy [17]. Our study revealed that βIII-tubulin is frequently overexpressed in mammary gland carcinoma after PTX and DOX treatment.…”

Section: Discussionmentioning

confidence: 68%

Influence of Paclitaxel and Doxorubicin Therapy of ßIII-Tubulin, Carbonic Anhydrase IX, and Survivin in Chemically Induced Breast Cancer in Female Rat

Pastornická

Rybárová

Drahošová

et al. 2021

IJMS

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Breast cancer is the most common cancer in females. The aim of this study was to determine the effect of paclitaxel (PTX) and doxorubicin (DOX) therapy on the βIII-tubulin, carbonic anhydrase IX (CA IX), and survivin expression in chemically-induced rat mammary tumors. Animals with induced mammary carcinogenesis were randomly divided into treatment groups and an untreated group. The total proportion of tumors, the proportion of carcinoma in situ (CIS), and invasive carcinoma (IC) were evaluated. Protein expression in tumor tissue was determined using IHC. Statistical analysis of the data, evaluated by Fisher-exact test and unpaired t-test. Significantly increased levels of proteins in the tumor cells were confirmed using the IHC method for all studied proteins. The expression of βIII-tubulin, CA IX, and survivin increased significantly after treatment with both cytostatics (PTX and DOX). Depending on the type of tumor, a significant increase in all proteins was observed in IC samples after PTX treatment, and CA IX expression after DOX treatment. In CIS samples, a significant increase of βIII-tubulin and survivin expression was observed after a DOX treatment. The results suggest that βIII-tubulin, survivin, and CA IX may be significant drug resistance markers and the clinical regulation of their activity may be an effective means of reversing this resistance.

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“…China has a high GC incidence and a heavy disease burden, with an estimated 320,000 annual deaths, accounting for 45% of all GC deaths globally [ 2 ]. Despite the constant iterations of comprehensive therapy based on surgical resection, GC prognosis remains poor, with a 5-year survival rate of not more than 30% [ 3 ]. On one hand, this is attributed to the malignant phenotype of the tumor; while on the other hand, the tumor microenvironment plays an essential role as an “accomplice” [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

A positive feedback loop between gastric cancer cells and tumor-associated macrophage induces malignancy progression

Piao

Wang

et al. 2022

J Exp Clin Cancer Res

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Background Hypoxia and inflammation tumor microenvironment (TME) play a crucial role in tumor development and progression. Although increased understanding of TME contributed to gastric cancer (GC) progression and prognosis, the direct interaction between macrophage and GC cells was not fully understood. Methods Hypoxia and normoxia macrophage microarrays of GEO database was analyzed. The peripheral blood mononuclear cell acquired from the healthy volunteers. The expression of C-X-C Motif Chemokine Ligand 8 (CXCL8) in GC tissues and cell lines was detected by quantitative reverse transcription PCR (qRT-PCR), western-blot, Elisa and immunofluorescence. Cell proliferation, migration, and invasion were evaluated by cell counting kit 8 (CCK8), colony formation, real-time imaging of cell migration and transwell. Flow Cytometers was applied to identify the source of cytokines. Luciferase reporter assays and chromatin immunoprecipitation were used to identify the interaction between transcription factor and target gene. Especially, a series of truncated and mutation reporter genes were applied to identify precise binding sites. The corresponding functions were verified in the complementation test and in vivo animal experiment. Results Our results revealed that hypoxia triggered macrophage secreted CXCL8, which induced GC invasion and proliferation. This macrophage-induced GC progression was CXCL8 activated C-X-C Motif Chemokine Receptor 1/2 (CXCR1/2) on the GC cell membrane subsequently hyperactivated Janus kinase 1/ Signal transducer and activator of transcription 1 (JAK/STAT1) signaling pathway. Then, the transcription factor STAT1 directly led to the overexpression and secretion of Interleukin 10 (IL-10). Correspondingly, IL-10 induced the M2-type polarization of macrophages and continued to increase the expression and secretion of CXCL8. It suggested a positive feedback loop between macrophage and GC. In clinical GC samples, increased CXCL8 predicted a patient’s pessimistic outcome. Conclusion Our work identified a positive feedback loop governing cancer cells and macrophage in GC that contributed to tumor progression and patient outcome.

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Microtubule Engagement with Taxane Is Altered in Taxane-Resistant Gastric Cancer

Cited by 24 publications

References 52 publications

Multicenter Phase II Study of Cabazitaxel in Advanced Gastroesophageal Cancer: Association of HER2 Expression and M2-Like Tumor-Associated Macrophages with Patient Outcome

Multicenter Phase II Study of Cabazitaxel in Advanced Gastroesophageal Cancer: Association of HER2 Expression and M2-Like Tumor-Associated Macrophages with Patient Outcome

Influence of Paclitaxel and Doxorubicin Therapy of ßIII-Tubulin, Carbonic Anhydrase IX, and Survivin in Chemically Induced Breast Cancer in Female Rat

A positive feedback loop between gastric cancer cells and tumor-associated macrophage induces malignancy progression

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