Differential Sensitivity of Glioma- versus Lung Cancer–Specific EGFR Mutations to EGFR Kinase Inhibitors

Vivanco, Igor; Robins, H. Ian; Rohle, Daniel; Campos, Carl; Grommes, Christian; Nghiemphu, Phioanh L.; Kubek, Sara; Oldrini, Barbara; Chheda, Milan G.; Yannuzzi, Nicolas A.; Tao, Hui; Zhu, Shaojun; Iwanami, Akio; Kuga, Daisuke; Dang, Julie; Pedraza, Alicia; Brennan, Cameron; Heguy, Adriana; Liau, Linda M.; Lieberman, Frank S.; Yung, W. K. Alfred; Gilbert, Mark R.; Reardon, David A.; Drappatz, Jan; Wen, Patrick Y.; Lamborn, Kathleen R.; Chang, Susan M.; Prados, Michael D.; Fine, Howard A.; Horvath, Steve; Wu, Nian; Lassman, Andrew B.; DeAngelis, Lisa M.; Yong, William H.; Kuhn, John G.; Mischel, Paul S.; Mehta, Minesh P.; Cloughesy, Timothy F.; Mellinghoff, Ingo K.

doi:10.1158/2159-8290.cd-11-0284

Cited by 300 publications

(276 citation statements)

References 46 publications

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“…Those discouraging results 62,63 probably explain why the usual dose is inadequate in the clinical setting. Vivanco et al 64 showed that the most frequent mutation of EGFR in gbm is relatively insensitive to erlotinib, being more sensitive to other egfr inhibitors (for example, HKI-272 or lapatinib).…”

Section: Inhibitors Of Egfr: Monotherapy or Combination?mentioning

confidence: 99%

Nonsurgical Treatment of Recurrent Glioblastoma

2015

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Standard treatment for glioblastoma multiforme is surgery followed by radiotherapy and chemotherapy, generally with temozolomide. However, disease recurs in almost all patients. Diagnosis of progression is complex given the possibility of pseudoprogression.The Response Assessment in Neuro-Oncology criteria increase the sensitivity for detecting progression. Most patients will not be candidates for new surgery or re-irradiation, and anticancer drugs are the most common approach for second-line treatment, if the patient's condition allows. Antiangiogenics, inhibitors of the epidermal growth factor receptor, nitrosoureas, and re-treatment with temozolomide have been studied in the second line, but a standard therapy has not yet been established. This review considers currently available medical treatment options for patients with glioblastoma recurrence.

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Section: Inhibitors Of Egfr: Monotherapy or Combination?mentioning

confidence: 99%

Nonsurgical Treatment of Recurrent Glioblastoma

2015

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“…However, the use of HER1/EGFR inhibitors targeting the inactive conformation of the receptor should be regarded with caution. So far, two clinical studies have failed to show a clinical benefit of lapatinib in the setting of recurrent glioblastoma (38,40). These results may be partly explained by the fact that mean tumor tissue concentrations of lapatinib were more than 10 times lower than those reported for erlotinib, which has a molecular size that is approximately half of that of lapatinib (38,41).…”

Section: U87mgmentioning

confidence: 98%

“…This finding is of particular interest because recently, two studies addressed the question why non-small cell lung cancer (NSCLC) and glioblastoma respond differently toward HER1/EGFR-targeted agents (38,39). Vivanco and colleagues showed that glioblastoma cell lines carrying glioblastoma-specific HER1/EGFR mutations were responsive toward an HER1/EGFR inhibitor directed against the inactive conformation of the catalytic tyrosine kinase domain, that is, lapatinib, an observation that contrasts with the findings in NSCLC cell lines (38). The authors concluded that the clinical failure of first-generation HER1/EGFR inhibitors in glioblastoma may be due to differences among NSCLC and glioblastoma in the conformational state of the receptor that is required for efficient inhibition.…”

Section: U87mgmentioning

confidence: 99%

“…So far, two clinical studies have failed to show a clinical benefit of lapatinib in the setting of recurrent glioblastoma (38,40). These results may be partly explained by the fact that mean tumor tissue concentrations of lapatinib were more than 10 times lower than those reported for erlotinib, which has a molecular size that is approximately half of that of lapatinib (38,41). Whether the combined treatment with lapatinib and NSC23766 exceeds the antineoplastic effects of erlotinib plus NSC23766 on glioblastoma cell lines harboring EGFRvIII is the subject of current investigations in our laboratory.…”

Section: U87mgmentioning

confidence: 99%

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Combined Inhibition of HER1/EGFR and RAC1 Results in a Synergistic Antiproliferative Effect on Established and Primary Cultured Human Glioblastoma Cells

Karpel‐Massler

Westhoff

Zhou

et al. 2013

Molecular Cancer Therapeutics

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Glioblastoma is the most frequent brain tumor of glial origin in adults. With the best available standard-ofcare, patients with this disease have a life expectancy of only approximately 15 months after diagnosis. Because the EGF receptor (HER1/EGFR) is one of the most commonly dysregulated oncogenes in glioblastoma, HER1/ EGFR-targeted agents, such as erlotinib, were expected to provide a therapeutic benefit. However, their application in the clinical setting failed. Seeking an explanation for this finding, we previously identified several candidate genes for resistance of human glioblastoma cell lines toward erlotinib. On the basis of this panel of genes, we aimed at identifying drugs that synergistically enhance the antiproliferative effect of erlotinib on established and primary glioblastoma cell lines. We found that NSC23766, an inhibitor of RAC1, enhanced the antineoplastic effects of erlotinib in U87MG, T98MG, and A172MG glioblastoma cell lines for the most part in a synergistic or at least in an additive manner. In addition, the synergistic antiproliferative effect of erlotinib and NSC23766 was confirmed in primary cultured cells, indicating a common underlying cellular and molecular mechanism in glioblastoma. Therefore, agents that suppress RAC1 activation may be useful therapeutic partners for erlotinib in a combined targeted treatment of glioblastoma.

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“…These are due to the compensatory mechanisms of alternative signaling pathways and cellular heterogeneity of glioblastoma as well as the insufficient penetration of drugs across the blood-brain barrier [215]. It is necessary to find another strategy that targets multiple genes simultaneously.…”

Section: Introductionmentioning

confidence: 99%

Identification and Characterization of miR-148a as a New Oncogenic and Prognostic microRNA in Glioblastoma

Kim

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Great interest persists in useful prognostic and therapeutic targets in glioblastoma (GBM), the most common and most deadly human brain tumor. In this study, we report the identification and characterization of microRNA-148a (miR-148a) as a novel prognostic oncomiR in GBM. We show that miR-148a expression is elevated in human GBM specimens, cell lines, and stem cells (GSC) compared with normal human brain and astrocytes. High levels of miR-148a were a risk indicator for GBM patient survival. Functionally, miR-148a expression increased cell growth, survival, migration, and invasion in glioblastoma cells and GSCs and promoted GSC neurosphere formation. We identified two direct targets of miR-148a, the EGF receptor (EGFR) regulator MIG6 and the apoptosis regulator BIM. Rescue experiments showed that MIG6 and BIM were essential to mediate the oncogenic activity of miR-148a. By inhibiting MIG6 expression, miR148a reduced EGFR trafficking to Rab7-expressing compartments, which includes late endosomes and lysosomes. This process coincided with reduced degradation and elevated expression and activation of EGFR. Finally, inhibition of miR-148a strongly suppressed GSC and glioblastoma xenograft growth in vivo. Taken together, our findings provide a comprehensive analysis of the prognostic value and oncogenic function of miR-148a in glioblastoma, further defining it as a potential target for glioblastoma therapy.

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Differential Sensitivity of Glioma- versus Lung Cancer–Specific EGFR Mutations to EGFR Kinase Inhibitors

Cited by 300 publications

References 46 publications

Nonsurgical Treatment of Recurrent Glioblastoma

Nonsurgical Treatment of Recurrent Glioblastoma

Combined Inhibition of HER1/EGFR and RAC1 Results in a Synergistic Antiproliferative Effect on Established and Primary Cultured Human Glioblastoma Cells

Identification and Characterization of miR-148a as a New Oncogenic and Prognostic microRNA in Glioblastoma

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