Loss of <i>ARID1A</i> Activates <i>ANXA1</i>, which Serves as a Predictive Biomarker for Trastuzumab Resistance

Berns, Katrien; Sonnenblick, Amir; Gennissen, Annemiek M.C.; Brohée, Sylvain; Hijmans, E. Marielle; Evers, Bastiaan; Fumagalli, Debora; Desmedt, Christine; Loibl, Sibylle; Denkert, Carsten; Neven, Patrick; Guo, Wei; Zhang, Fan; Knijnenburg, Theo; Bosse, Tjalling; Heijden, Michiel S. van der; Hindriksen, Sanne; Nijkamp, Wouter; Wessels, Lodewyk; Joensuu, Heikki; Mills, Gordon B.; Beijersbergen, Roderick L.; Sotiriou, Christos; Bernards, René

doi:10.1158/1078-0432.ccr-15-2996

Cited by 42 publications

(36 citation statements)

References 47 publications

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“…Of these, ANXA1 , CLU, SLC17A1 and RCAN1 encode for stress proteins [ 13 – 16 ]. ANXA1, ANXA3, CLU and CTGF are associated with drug resistance [ 17 – 20 ]. Interestingly, upregulation of cell migration-inducing protein (CEMIP) has been associated with enhanced cell migration [ 21 ].…”

Section: Resultsmentioning

confidence: 99%

Personalized therapy: CNS HGNET-BCOR responsiveness to arsenic trioxide combined with radiotherapy

et al. 2017

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High-grade neuroepithelial tumor of the central nervous system with BCOR alteration (HGNET-BCOR) is a rare, highly malignant tumor. At the time of this publication, no standard protocol exists to treat this tumor entity. In this work, we tested the responsiveness of the primary culture PhKh1 derived from tumor tissue from a pediatric HGNET-BCOR patient (P1) to inhibitors of the Sonic hedgehog pathway combined with radiation. The SMO inhibitors vismodegib and itraconazole had low effect on the proliferation of the PhKh1 cells. However, the GLI inhibitor arsenic trioxide reduced the expression of GLI target genes in the PhKh1 cells and in combination with radiotherapy significantly decreased their clonogenic potential. PhKh1 cells resistant to arsenic trioxide were characterized by the overexpression of molecular chaperones. We combined arsenic trioxide and radiation in the relapse therapy protocol of P1, achieving complete remission after seven weeks. Clinical remission lasted for six months, when P1 developed systemic metastases. Meanwhile, an increase in the concentration of circulating tumor DNA carrying a BCOR internal tandem duplication was observed. Molecular characterization of a second patient (P2) was also performed. In P2, we detected a larger tandem duplication and greater activation of the Sonic hedgehog pathway than in P1. These findings suggest that combining arsenic trioxide with radiotherapy may represent a new therapeutic approach. Moreover, peripheral blood analysis for circulating tumor DNA could help in the early detection of systemic metastases.

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Section: Resultsmentioning

confidence: 99%

Personalized therapy: CNS HGNET-BCOR responsiveness to arsenic trioxide combined with radiotherapy

et al. 2017

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“…ARID1A is one of the most frequently mutated genes in human cancers and is present in 7% of lung adenocarcinomas [27] . Previous studies observed that loss of ARID1A was correlated with resistance to the ERBB2-targeting antibody trastuzumab by activating the AKT pathway [28] . In this study, we observed the outbreak of multiple missense mutations and one function-impairing fusion in ARID1A in patient #SR01.…”

Section: Discussionmentioning

confidence: 97%

Short-Term Responders of Non–Small Cell Lung Cancer Patients to EGFR Tyrosine Kinase Inhibitors Display High Prevalence of TP53 Mutations and Primary Resistance Mechanisms

Tong²,

Yan³

et al. 2018

Translational Oncology

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Non–small cell lung cancer (NSCLC) with activating EGFR mutations in exon 19 and 21 typically responds to EGFR tyrosine kinase inhibitors (TKI); however, for some patients, responses last only a few months. The underlying mechanisms of such short responses have not been fully elucidated. Here, we sequenced the genomes of 16 short-term responders (SR) that had progression-free survival (PFS) of less than 6 months on the first-generation EGFR TKI and compared them to 12 long-term responders (LR) that had more than 24 months of PFS. All patients were diagnosed with advanced lung adenocarcinoma and harbored EGFR 19del or L858R mutations before treatment. Paired tumor samples collected before treatment and after relapse (or at the last follow-up) were subjected to targeted next-generation sequencing of 416 cancer-related genes. SR patients were significantly younger than LR patients (P < .001). Collectively, 88% of SR patients had TP53 variations compared to 13% of LR patients (P < .001). Additionally, 37.5% of SR patients carried EGFR amplifications compared to 8% of LR patients. Other potential primary resistance factors were also identified in the pretreatment samples of 12 SR patients (75%), including PTEN loss; BIM deletion polymorphism; and amplifications of EGFR, ERBB2, MET, HRAS, and AKT2. Comparatively, only three LR patients (25%) were detected with EGFR or AKT1 amplifications that could possibly exert resistance. The diverse preexisting resistance mechanisms in SR patients revealed the complexity of defining treatment strategies even for EGFR-sensitive mutations.

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“…RPE-1, HCT-116, U2OS, CAL51, MDA-MB-231, MCF7, BT20, CAL-120, and SKBR-3 were grown in DMEM (Lonza, Basel, Switzerland), and HCC1937, HCC1187, HCC1806, HCC1395, T47D, BT-549, HCC70, and HS578T were grown in Gibco Advanced RPMI 1640 medium (Fisher Scientific) supplemented with 6% fetal calf serum (Clontech, Mountain View, CA, USA), 50μg/ml penicillin–streptomycin (Invitrogen, Waltham, MA, USA) and 2 mM L-glutamine (Lonza). RPE-11 was obtained from the American Type Culture Collection, and the breast cancer cell lines described in [ 42 , 43 ]. All cell lines were tested for mycoplasma contamination every three months.…”

Section: Methodsmentioning

confidence: 99%

TUBB3 overexpression has a negligible effect on the sensitivity to taxol in cultured cell lines

et al. 2017

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Microtubules are cellular targets for a variety of anticancer therapies because of their critical function in mitosis. Taxol belongs to a class of microtubule targeting agents that suppresses microtubule dynamics and interferes with the functioning of the mitotic spindle, thereby effectively blocking cell cycle progression of rapidly proliferating tumor cells. Despite its antitumor activity, drug resistance remains a common obstacle in improving its overall clinical efficacy. Previous studies have shown that the expression of a specific β-tubulin isotype, βIII-tubulin/TUBB3, is dysregulated in drug-refractory tumors. However, whether enhanced TUBB3 expression is directly involved in promoting taxol resistance remains a subject of debate. Here, we have used several approaches to assess the functional relation of TUBB3 overexpression and taxol resistance. First, we generated a number of taxol-resistant cell lines, to find that TUBB3 expression was elevated in a resistant cell line (RPE-20) derived from untransformed retinal pigment epithelial (RPE) cells, but the abundance of TUBB3 remained unchanged in four other cell lines after taxol treatment. However, although RPE-20 cells displayed enhanced TUBB3 levels, we find that simultaneous up-regulation of the P-glycoprotein (P-gP) drug-efflux pump is responsible for the resistance to taxol. Indeed, we could show that TUBB3 levels were dynamically regulated upon taxol exposure and withdrawal, unrelated to the resistance phenotype. Next, we generated cell lines in which we could induce robust overexpression of TUBB3 from its endogenous locus employing the CRISPRa system. We demonstrate that solely enhancing TUBB3 expression results in a very minor decrease in the sensitivity to taxol. This was further substantiated by selective depletion of TUBB3 in a series of breast cancer cell lines expressing high levels of TUBB3. We find that TUBB3 depletion had a minimal effect on the sensitivity to taxol in one of these cell lines, but had no effect in all of the others. Based on these findings we propose that TUBB3 overexpression can only marginally affect the sensitivity to taxol in cultured cell lines.

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Loss of ARID1A Activates ANXA1, which Serves as a Predictive Biomarker for Trastuzumab Resistance

Cited by 42 publications

References 47 publications

Personalized therapy: CNS HGNET-BCOR responsiveness to arsenic trioxide combined with radiotherapy

Personalized therapy: CNS HGNET-BCOR responsiveness to arsenic trioxide combined with radiotherapy

Short-Term Responders of Non–Small Cell Lung Cancer Patients to EGFR Tyrosine Kinase Inhibitors Display High Prevalence of TP53 Mutations and Primary Resistance Mechanisms

TUBB3 overexpression has a negligible effect on the sensitivity to taxol in cultured cell lines

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