Unbiased Proteomic Profiling Uncovers a Targetable GNAS/PKA/PP2A Axis in Small Cell Lung Cancer Stem Cells

Coles, Garry L.; Cristea, Sandra; Webber, James T.; Levin, Rebecca S.; Moss, Steven M.; He, Andy; Sangodkar, Jaya; Hwang, Yeonjoo; Arand, Julia; Drainas, Alexandros P.; Mooney, Nancie A.; Demeter, János; Spradlin, Jessica N.; Mauch, Brandon; Le, Vicky; Shue, Yan Ting; Ko, Julie; Lee, Myung Chang; Kong, Christina S.; Nomura, Daniel K.; Ohlmeyer, Michael; Swaney, Danielle L.; Krogan, Nevan J.; Jackson, Peter K.; Narla, Goutham; Gordan, John D.; Shokat, Kevan M.; Sage, Julien

doi:10.1016/j.ccell.2020.05.003

Cited by 71 publications

(83 citation statements)

References 111 publications

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“…Related studies have delineated the essential role of PKAc as its effector (Coles et al, 2020;Patra et al, 2018). Here, we define the context of genetic alterations in PRKACA and PRKAR1A that result in PKAc activation in cancer and a set of conserved pathways downstream oncogenic PKAc signaling.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic PKA signaling stabilizes MYC oncoproteins via an aurora kinase A-dependent mechanism

Chan

Maisel

Hwang

et al. 2021

Preprint

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Genetic alterations that activate protein kinase A (PKA) signaling are found across many tumor types, but their downstream oncogenic mechanisms are poorly understood. We used global phosphoproteomics and kinome activity profiling to map the conserved signaling outputs driven by diverse genetic changes that activate PKA in human cancer, including melanoma and fibrolamellar carcinoma (FLC). We define two consensus networks of effectors downstream of PKA in cancer models. One is centered on RAS/MAPK components, and a second involves Aurora Kinase A (AURKA). We find that AURKA stabilizes c-MYC and n-MYC protein levels and expression programs in PKA-dependent tumor models, in part via a positive feedback loop mediated by the oncogenic kinase PIM2. This process can be suppressed by conformation-disrupting AURKA inhibitors such as CD-532. Our findings elucidate two independent mechanisms of PKA-driven tumor cell growth and offer insight into drug targets for study in FLC and other PKA-dependent malignancies.

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Section: Discussionmentioning

confidence: 99%

Oncogenic PKA signaling stabilizes MYC oncoproteins via an aurora kinase A-dependent mechanism

Chan

Maisel

Hwang

et al. 2021

Preprint

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“…Due to the plasticity of CSCs, Stationary CSCs may produce cycling CSCs, leading to cancer recurrence [21] . Studies have shown that PKA activation promotes CSC state in small cell lung cancer [22] . In colorectal cancer, CSC evades treatment-mediated DNA damage by changing cell cycle checkpoints, increasing DNA damage repair capabilities, and effectively removing reactive oxygen species [23] .…”

Section: Discussionmentioning

confidence: 99%

LncRNA MONC suppresses the malignant phenotype of Endometrial Cancer Stem Cells and Endometrial Carcinoma Cells by regulating the MiR-636/GLCE axis

Huo

et al. 2021

Preprint

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Background Emerging evidence shows that abnormal expression of long non-coding RNA is involved in the occurrence and development of various tumors. LncRNA MONC is abnormally expressed in head and neck squamous cell carcinoma, lung cancer, colorectal cancer, and acute megakaryocytic leukemia, but the biological function and potential regulatory mechanism of MONC in endometrial cancer stem cells (ECSCs) and endometrial cancer cells (ECCs) have not been studied. Methods We used qRT-PCR to detect the expression of MONC, miR-636 and GLCE in normal human endometrial tissues and endometrial carcinoma tissues. Luciferase assay was used to verify the binding sites between MONC and miR-636 and between miR-636 and GLCE. The double fluorescence in situ hybridization was used to locate MONC and miR-636 in cells. Endometrial cancer stem cells were obtained by Flow cytometry sorting assay. Sphere formation assay, CCK-8 assay, transwell invasion assay, cell cycle analysis and apoptosis assay were used to detect the effects of MONC/miR-636/GLCE axis on the malignant biological behavior of ECSCs and endometrial carcinoma cells (ECCs). The effect of MONC on the epithelial-to-mesenchymal transition (EMT) process was detected using western blot. Finally, we conducted in vivo verification through Tumor xenografts in nude mice. Results In this study, we aimed to explore the tumor suppressive effect and mechanism of MONC in regulating ECSCs and ECCs. We found MONC is low expression in endometrial carcinoma (EC), MONC and miR-636 are relatively co-localized in the cytoplasm. MONC directly inhibits the malignant biological behavior of ECSCs and ECCs by directly inhibiting miR-636. Simultaneously, miR-636 may indirectly reduce the expression of MONC. Down-regulation of miR-636 may promote GLCE expression by targeting the 3'-untranslated region (UTR) of the downstream gene GLCE, thereby inhibiting the progression of ECSCs. MONC combined with miR-636 inhibited tumor epithelial-to-mesenchymal transition (EMT) process. In addition, we verified the tumor suppressive effect of MONC in nude mice, miR-636 can rescue the tumor suppressive effect of overexpressing MONC. Conclusions In conclusion, this study shows that MONC inhibits the malignant phenotypes of ECSCs and ECCs by regulating the miR-636/GLCE axis. The MONC/miR-636/GLCE axis may provide novel treatment avenues for human EC.

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“…Furthermore, Hijazi and colleagues used chemical phosphoproteomics to reveal that while PIK3CA wild-type cells seem to depend on MAPK pathway activation, PIK3CA mutant cells more predominantly rely on AKT and mTOR signaling outputs for survival [ 271 ]. Moreover, phosphoproteomics analysis identified the protein kinase A (PKA)-regulated signaling network as pro-tumorigenic circuitry in G-protein α subunit (GNAS)-mutated small cell lung cancer cells [ 272 ]. Through phosphoproteomics, we recently found that the loss of PTEN protein phosphatase activity leads to an enrichment of phospho-peptides regulated by the glucocorticoid receptor, GR, and confirmed that GR activation sensitizes mutant PTEN cells to death [ 139 ].…”

Section: How Can Technological Advances Assist With the Identificamentioning

confidence: 99%

Signaling Pathways in Cancer: Therapeutic Targets, Combinatorial Treatments, and New Developments

Yip

Papa

2021

Cells

144

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Molecular alterations in cancer genes and associated signaling pathways are used to inform new treatments for precision medicine in cancer. Small molecule inhibitors and monoclonal antibodies directed at relevant cancer-related proteins have been instrumental in delivering successful treatments of some blood malignancies (e.g., imatinib with chronic myelogenous leukemia (CML)) and solid tumors (e.g., tamoxifen with ER positive breast cancer and trastuzumab for HER2-positive breast cancer). However, inherent limitations such as drug toxicity, as well as acquisition of de novo or acquired mechanisms of resistance, still cause treatment failure. Here we provide an up-to-date review of the successes and limitations of current targeted therapies for cancer treatment and highlight how recent technological advances have provided a new level of understanding of the molecular complexity underpinning resistance to cancer therapies. We also raise three basic questions concerning cancer drug discovery based on molecular markers and alterations of selected signaling pathways, and further discuss how combination therapies may become the preferable approach over monotherapy for cancer treatments. Finally, we consider novel therapeutic developments that may complement drug delivery and significantly improve clinical response and outcomes of cancer patients.

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Unbiased Proteomic Profiling Uncovers a Targetable GNAS/PKA/PP2A Axis in Small Cell Lung Cancer Stem Cells

Abstract: Highlights d PKA inhibition or PP2A activation inhibits SCLC growth d The GNAS/PKA axis promotes SCLC growth d Proteomics studies uncover widespread PKA targets and downstream signaling networks d PKA activation promotes a cancer stem cell state

Cited by 71 publications

References 111 publications

Oncogenic PKA signaling stabilizes MYC oncoproteins via an aurora kinase A-dependent mechanism

Oncogenic PKA signaling stabilizes MYC oncoproteins via an aurora kinase A-dependent mechanism

LncRNA MONC suppresses the malignant phenotype of Endometrial Cancer Stem Cells and Endometrial Carcinoma Cells by regulating the MiR-636/GLCE axis

Signaling Pathways in Cancer: Therapeutic Targets, Combinatorial Treatments, and New Developments

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