Combination therapy with potent PI3K and MAPK inhibitors overcomes adaptive kinome resistance to single agents in preclinical models of glioblastoma

McNeill, Robert S.; Canoutas, Demitra A.; Stuhlmiller, Timothy J.; Dhruv, Harshil D.; Irvin, David M.; Bash, Ryan; Herring, Laura E.; Simon, Jeremy M.; Skinner, Kasey R; Limas, Juanita C.; Chen, Xin; Schmid, Ralf S.; Siegel, Marni B.; Swearingen, Amanda E.D. Van; Hadler, Michael; Sulman, Erik P.; Sarkaria, Jann N.; Anders, Carey K.; Graves, Lee M.; Berens, Michael E.; Johnson, Gary L.; Miller, C. Ryan

doi:10.1093/neuonc/nox044

Cited by 43 publications

(50 citation statements)

References 41 publications

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“…Accordingly, the PI3K/Akt pathway is an ideal target for cancer therapy [41]. At present, the PI3K/Akt inhibitor has been applied to cancer therapy in preclinical trials [41,43,44]. In this study, the results of RNA-seq and GEO data revealed that the PI3K/Akt pathway was activated after cobimetinib treatment of HCT116 cells.…”

Section: Discussionmentioning

confidence: 76%

Efficacy of the MEK Inhibitor Cobimetinib and its Potential Application to Colorectal Cancer Cells

Gong

Zhu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Mutations in the Ras/Raf/MEK/ERK pathway are detected in 50% of colorectal cancer cases and play a crucial role in cancer development and progression. Cobimetinib is a MEK inhibitor approved for the treatment of advanced melanoma and inhibits the cell viability of other types of cancer cells. Methods: HCT116 colorectal cancer cells were treated with cobimetinib, and MTT assay, colony formation assay, and flow cytometry were used to evaluate cell viability, cell cycle, and apoptosis, respectively. The expression of genes associated with the cell cycle and apoptosis were evaluated by quantitative real-time PCR and western blotting. To explore use of cobimetinib in colorectal cancer treatment and further understand its mechanisms, RNA-seq technology was used to identify differentially expressed genes (DEGs) between cobimetinib-treated and untreated HCT116 cells. Furthermore, we compared these DEGs with Gene Expression Omnibus data from colorectal cancer tissues and normal colonic epithelial tissues. Results: We found that cobimetinib not only inhibited cell proliferation but also induced G1 phase arrest and apoptosis in HCT116 colorectal cancer cells, suggesting that cobimetinib may useful in colorectal cancer therapy. After cobimetinib treatment, 3,495 DEGs were obtained, including 2,089 upregulated genes and 1,406 downregulated genes, and most of these DEGs were enriched in the cell cycle, DNA replication, and DNA damage repair pathways. Our results revealed that some genes with high expression in colorectal cancer tissues were downregulated by cobimetinib in HCT116 cells, including CCND1, E2F1, CDC25C, CCNE2, MYC, and PCNA. These genes have vital roles in DNA replication and the cell cycle. Furthermore, genes with low expression in colorectal cancer tissues were upregulated by cobimetinib, including PRKCA, PI3K, RTK, and PKC. Based on our results, the PKC and PI3K pathways were activated after cobimetinib treatment, and inhibition of these two pathways can increase the cytotoxicity of cobimetinib in HCT116 cells. Notably, cobimetinib appeared to enhance the efficacy of 5-fluorouracil (5-FU) by decreasing TYMS expression, high expression of which is responsible for 5-FU resistance in colorectal cancer. Conclusions: Our results suggest the potential use of cobimetinib in colorectal cancer therapy.

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Section: Discussionmentioning

confidence: 76%

Efficacy of the MEK Inhibitor Cobimetinib and its Potential Application to Colorectal Cancer Cells

Gong

Zhu

et al. 2018

Cell Physiol Biochem

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“…Accumulating evidence from studies in GBM suggests that PI3K and MAPK are reciprocal bypass pathways that can promote resistance to drugs targeting either pathway alone (40)(41)(42)(43). Receptor tyrosine kinase (RTK)/PI3K/MAPK pathways are frequently mutated in solid tumors such as GBM (44), and PI3K and MAPK promote cancer hallmarks, such as uncontrolled growth, survival, and migration (7,45,46).…”

Section: Discussionmentioning

confidence: 99%

“…Receptor tyrosine kinase (RTK)/PI3K/MAPK pathways are frequently mutated in solid tumors such as GBM (44), and PI3K and MAPK promote cancer hallmarks, such as uncontrolled growth, survival, and migration (7,45,46). However, combined PI3K and MAPK/ERK kinase (MEK) inhibition frequently induced systemic toxicity, limiting the effectiveness of these drug combinations (40,47).…”

Section: Discussionmentioning

confidence: 99%

“…The absence of drug-related adverse reactions in xenograft models suggests that the combination treatment might be well tolerated. As combined PI3K and MEK inhibition is known to induce toxicity (40,47), specific targeting of the a isoform of PI3K and the MEK downstream effector MNK might offer a wider therapeutic window while still effectively blocking medulloblastoma growth. CSCs have been implicated in the emergence of resistance and tumor relapse in multiple solid tumors (36).…”

Section: Discussionmentioning

confidence: 99%

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Potent Antineoplastic Effects of Combined PI3Kα–MNK Inhibition in Medulloblastoma

Eckerdt

Bell

Beauchamp

et al. 2019

Molecular Cancer Research

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Medulloblastoma is a highly malignant pediatric brain tumor associated with poor outcome. Developing treatments that target the cancer stem cell (CSC) population in medulloblastoma are important to prevent tumor relapse and induce long-lasting clinical responses. We utilized medulloblastoma neurospheres that display CSC characteristics and found activation of the PI3K/AKT pathway in sphere-forming cells. Of all class I A PI3Ks, only the PI3Ka isoform was required for sphere formation by medulloblastoma cells. Knockdown of p110a, but not p110b or p110d, significantly disrupted cancer stem cell frequencies as determined by extreme limiting dilution analysis (ELDA), indicating an essential role for the PI3Ka catalytic isoform in medulloblastoma CSCs. Importantly, pharmacologic inhibition of the MAPK-interacting kinase (MNK) enhanced the antineoplastic effects of targeted PI3Ka inhibition in medulloblastoma. This indicates that MNK signaling promotes survival in medulloblastoma, suggesting dual PI3Ka and MNK inhibition may provide a novel approach to target and eliminate medulloblastoma CSCs. We also observed a significant reduction in tumor formation in subcutaneous and intracranial mouse xenograft models, which further suggests that this combinatorial approach may represent an efficient therapeutic strategy for medulloblastoma.Implications: These findings raise the possibility of a unique therapeutic approach for medulloblastoma, involving MNK targeting to sensitize medulloblastoma CSCs to PI3Ka inhibition.

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“…Combined with quantitative methods of mass spectrometry (MS), MIB/MS was used to measure changes in the kinome in response to targeted kinase inhibitors and acquired drug resistance [Duncan et al, 2012;Cooper et al, 2013;Stuhlmiller et al, 2015;Kurimchak et al, 2016;McNeill et al, 2017;Zawistowski et al, 2017]. Based on changes in MIB kinase binding in response to EGF and pervanadate, the ability of MIB/MS to measure changes in the activity of individual kinases was reported.…”

Section: Multiplexed Inhibitor Beadsmentioning

confidence: 99%

Measuring Kinase Activity—A Global Challenge

Cann

McDonald

East

et al. 2017

J of Cellular Biochemistry

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The kinase enzymes within a cell, known collectively as the kinome, play crucial roles in many signaling pathways, including survival, motility, differentiation, stress response, and many more. Aberrant signaling through kinase pathways is often linked to cancer, among other diseases. A major area of scientific research involves understanding the relationships between kinases, their targets, and how the kinome adapts to perturbations of the cellular system. This review will discuss many of the current and developing methods for studying kinase activity, and evaluate their applications, advantages, and disadvantages. J. Cell. Biochem. 118: 3595-3606, 2017. © 2017 Wiley Periodicals, Inc.

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Combination therapy with potent PI3K and MAPK inhibitors overcomes adaptive kinome resistance to single agents in preclinical models of glioblastoma

Abstract: Drug potency influences PI3K/MEK inhibitor-induced target inhibition, adaptive kinome reprogramming, efficacy, and synergy. Our findings suggest that combination therapies with highly potent, brain-penetrant kinase inhibitors will be required to improve patient outcomes.

Cited by 43 publications

References 41 publications

Efficacy of the MEK Inhibitor Cobimetinib and its Potential Application to Colorectal Cancer Cells

Efficacy of the MEK Inhibitor Cobimetinib and its Potential Application to Colorectal Cancer Cells

Potent Antineoplastic Effects of Combined PI3Kα–MNK Inhibition in Medulloblastoma

Measuring Kinase Activity—A Global Challenge

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