Dataset Information

Protein kinase C_ι and SRC signaling define reciprocally related subgroups of glioblastoma with distinct therapeutic vulnerabilities.

ABSTRACT: We report that atypical protein kinase Cι (PKCι) is an oncogenic driver of glioblastoma (GBM). Deletion or inhibition of PKCι significantly impairs tumor growth and prolongs survival in murine GBM models. GBM cells expressing elevated PKCι signaling are sensitive to PKCι inhibitors, whereas those expressing low PKCι signaling exhibit active SRC signaling and sensitivity to SRC inhibitors. Resistance to the PKCι inhibitor auranofin is associated with activated SRC signaling and response to a SRC inhibitor, whereas resistance to a SRC inhibitor is associated with activated PKCι signaling and sensitivity to auranofin. Interestingly, PKCι- and SRC-dependent cells often co-exist in individual GBM tumors, and treatment of GBM-bearing mice with combined auranofin and SRC inhibitor prolongs survival beyond either drug alone. Thus, we identify PKCι and SRC signaling as distinct therapeutic vulnerabilities that are directly translatable into an improved treatment for GBM.

SUBMITTER: Kenchappa RS

PROVIDER: S-EPMC9845019 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Protein kinase C<sub>ι</sub> and SRC signaling define reciprocally related subgroups of glioblastoma with distinct therapeutic vulnerabilities.

Kenchappa Rajappa S RS Liu Yi Y Argenziano Michael G MG Banu Matei A MA Mladek Ann C AC West Rita R Luu Amanda A Quiñones-Hinojosa Alfredo A Hambardzumyan Dolores D Justilien Verline V Leitges Michael M Sarkaria Jann N JN Sims Peter A PA Canoll Peter P Murray Nicole R NR Fields Alan P AP Rosenfeld Steven S SS

Cell reports 20211101 8

We report that atypical protein kinase Cι (PKCι) is an oncogenic driver of glioblastoma (GBM). Deletion or inhibition of PKCι significantly impairs tumor growth and prolongs survival in murine GBM models. GBM cells expressing elevated PKCι signaling are sensitive to PKCι inhibitors, whereas those expressing low PKCι signaling exhibit active SRC signaling and sensitivity to SRC inhibitors. Resistance to the PKCι inhibitor auranofin is associated with activated SRC signaling and response to a SRC ...[more]

PMID: 34818553

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Project description:The inhibitory epidermal growth factor receptor (EGFR) antibody, cetuximab, is an approved therapy for head and neck squamous cell carcinoma (HNSCC). Despite tumor response observed in some HNSCC patients, cetuximab alone or combined with radio- or chemotherapy fails to yield long-term control or cures. We hypothesize that a flexible receptor tyrosine kinase coactivation signaling network supports HNSCC survival in the setting of EGFR blockade, and that drugs disrupting this network will provide superior tumor control when combined with EGFR inhibitors. In this work, we submitted EGFR-dependent HNSCC cell lines to RNA interference-based functional genomics screens to identify, in an unbiased fashion, essential protein kinases for growth and survival as well as synthetic lethal targets for combined inhibition with EGFR antagonists. Mechanistic target of rapamycin kinase (MTOR) and erythroblastosis oncogene B (ERBB)3 were identified as high-ranking essential kinase hits in the HNSCC cell lines. MTOR dependency was confirmed by distinct short hairpin RNAs (shRNAs) and high sensitivity of the cell lines to AZD8055, whereas ERBB3 dependency was validated by shRNA-mediated silencing. Furthermore, a synthetic lethal kinome shRNA screen with a pan-ERBB inhibitor, AZD8931, identified multiple components of the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase pathway, consistent with ERK reactivation and/or incomplete ERK pathway inhibition in response to EGFR inhibitor monotherapy. As validation, distinct mitogen-activated protein kinase kinase (MEK) inhibitors yielded synergistic growth inhibition when combined with the EGFR inhibitors, gefitinib and AZD8931. The findings identify ERBB3 and MTOR as important pharmacological vulnerabilities in HNSCC and support combining MEK and EGFR inhibitors to enhance clinical efficacy in HNSCC. SIGNIFICANCE STATEMENT: Many cancers are driven by nonmutated receptor tyrosine kinase coactivation networks that defy full inhibition with single targeted drugs. This study identifies erythroblastosis oncogene B (ERBB)3 as an essential protein kinase in epidermal growth factor receptor-dependent head and neck squamous cell cancer (HNSCC) cell lines and a synthetic lethal interaction with the extracellular signal-regulated kinase mitogen-activated protein kinase pathway that provides a rationale for combining pan-ERBB and mitogen-activated protein kinase inhibitors as a therapeutic approach in subsets of HNSCC.

Dataset Information

Protein kinase C_ι and SRC signaling define reciprocally related subgroups of glioblastoma with distinct therapeutic vulnerabilities.

Publications

Protein kinase C<sub>ι</sub> and SRC signaling define reciprocally related subgroups of glioblastoma with distinct therapeutic vulnerabilities.

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Dataset Information

Protein kinase Cι and SRC signaling define reciprocally related subgroups of glioblastoma with distinct therapeutic vulnerabilities.

Publications

Protein kinase C<sub>ι</sub> and SRC signaling define reciprocally related subgroups of glioblastoma with distinct therapeutic vulnerabilities.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Protein kinase C_ι and SRC signaling define reciprocally related subgroups of glioblastoma with distinct therapeutic vulnerabilities.