Combinations of BRAF, MEK, and PI3K/mTOR Inhibitors Overcome Acquired Resistance to the BRAF Inhibitor GSK2118436 Dabrafenib, Mediated by<i>NRAS</i>or<i>MEK</i>Mutations

Greger, James; Eastman, Stephen D.; Zhang, Vivian; Bleam, Maureen R.; Hughes, Ashley M.; Smitheman, Kimberly N.; Dickerson, Scott H.; Laquerre, Sylvie; Liu, Li; Gilmer, Tona M.

doi:10.1158/1535-7163.mct-11-0989

Cited by 319 publications

(278 citation statements)

References 41 publications

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“…It has recently been demonstrated that cotargeting of the MEK/ERK and PI3K/mTOR pathways with MEKi+AKTi and MEKi+mTORi 1 is effective in BRAF mutant cells with acquired resistance to BRAF inhibitors due to activating mutations in NRAS (26,27). Although these combinations also decreased cell growth in our panel of 10 human NRAS mutant melanoma cell lines, we observed that it was less effective in decreasing cell viability than MEKi+PI3K/mTORi 1,2 .…”

Section: Discussionmentioning

confidence: 58%

Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo

Posch

Moslehi

Feeney

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

206

214

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Activating mutations in the neuroblastoma rat sarcoma viral oncogene homolog (NRAS) gene are common genetic events in malignant melanoma being found in 15-25% of cases. NRAS is thought to activate both mitogen activated protein kinase (MAPK) and PI3K signaling in melanoma cells. We studied the influence of different components on the MAP/extracellular signal-regulated (ERK) kinase (MEK) and PI3K/mammalian target of rapamycin (mTOR)-signaling cascade in NRAS mutant melanoma cells. In general, these cells were more sensitive to MEK inhibition compared with inhibition in the PI3K/ mTOR cascade. Combined targeting of MEK and PI3K was superior to MEK and mTOR 1,2 inhibition in all NRAS mutant melanoma cell lines tested, suggesting that PI3K signaling is more important for cell survival in NRAS mutant melanoma when MEK is inhibited. However, targeting of PI3K/mTOR 1,2 in combination with MEK inhibitors is necessary to effectively abolish growth of NRAS mutant melanoma cells in vitro and regress xenografted NRAS mutant melanoma. Furthermore, we showed that MEK and PI3K/mTOR 1,2 inhibition is synergistic. Expression analysis confirms that combined MEK and PI3K/mTOR 1,2 inhibition predominantly influences genes in the rat sarcoma (RAS) pathway and growth factor receptor pathways, which signal through MEK/ERK and PI3K/mTOR, respectively. Our results suggest that combined targeting of the MEK/ERK and PI3K/mTOR pathways has antitumor activity and might serve as a therapeutic option in the treatment of NRAS mutant melanoma, for which there are currently no effective therapies.O ncogenic mutations in codons 12, 13, or 61 of the rat sarcoma (RAS) family of small GTPases, Kirsten rat sarcoma viral oncogene homolog (KRAS), Harvey rat sarcoma viral oncogene homolog (HRAS), and neuroblastoma RAS viral oncogene homolog (NRAS) occur in approximately one-third of all human cancers with NRAS mutations found in about 15-20% of melanomas (1-7). Mutated RAS proteins activate signaling pathways that promote the cell division cycle and cell growth and suppress apoptosis. Small interfering RNA (siRNA)-mediated depletion of NRAS in melanoma cell lines inhibits proliferation and renders cells sensitive to chemotherapy, making mutant NRAS and its signaling effectors relevant targets for melanoma therapy (8, 9). Efforts at developing therapeutics that inhibit mutant RAS directly have so far not been successful. The high affinity of RAS for GTP and the high concentrations of GTP intracellularly has meant that the identification of small molecules, which selectively prevent accumulation of RAS-GTP, has not been possible (10). Targeting mutant NRAS with siRNA is still limited to preclinical models because of the significant challenge in delivering antisense oligonucleotides in vivo. The response of NRAS mutant melanoma and other melanomas to various chemotherapeutic regiments has been very scarce with only 6% of patients responding (11). Alternatively, farnesyltransferase inhibitors (FTIs) were thought to inhibit RAS activation by blocking farnesy...

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Section: Discussionmentioning

confidence: 58%

Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo

Posch

Moslehi

Feeney

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

206

214

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“…MEK1/2 inhibitors used with EGFR or VEGFR TKIs have demonstrated growth inhibition, antiangiogenesis, and curbed metastasis. Resistance to a BRAF inhibitor (BRAFi) dabrafenib, attributed to mutations in NRAS or MEK, was restored when melanoma cells were co-treated with dabrafenib and a MEK inhibitor (MEKi) trametinib [92,93]. This combination treatment was subsequently approved by the FDA in 2014 for therapy for advanced melanoma.…”

Section: Simultaneously Targeting Major Oncogenic Pathways By Multiplmentioning

confidence: 99%

“Combo” nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy

Kemp

Shim

Heo

et al. 2016

Advanced Drug Delivery Reviews

437

258

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a b s t r a c t a r t i c l e i n f oThe dynamic and versatile nature of diseases such as cancer has been a pivotal challenge for developing efficient and safe therapies. Cancer treatments using a single therapeutic agent often result in limited clinical outcomes due to tumor heterogeneity and drug resistance. Combination therapies using multiple therapeutic modalities can synergistically elevate anti-cancer activity while lowering doses of each agent, hence, reducing side effects. Co-administration of multiple therapeutic agents requires a delivery platform that can normalize pharmacokinetics and pharmacodynamics of the agents, prolong circulation, selectively accumulate, specifically bind to the target, and enable controlled release in target site. Nanomaterials, such as polymeric nanoparticles, gold nanoparticles/cages/shells, and carbon nanomaterials, have the desired properties, and they can mediate therapeutic effects different from those generated by small molecule drugs (e.g., gene therapy, photothermal therapy, photodynamic therapy, and radiotherapy). This review aims to provide an overview of developing multi-modal therapies using nanomaterials ("combo" nanomedicine) along with the rationale, up-to-date progress, further considerations, and the crucial roles of interdisciplinary approaches.

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“…Another approach is to target multiple signaling pathways simultaneously, and thus prevent the cancer cell from changing its dependency to another signaling pathway. There is considerable preclinical evidence supporting this approach, for example, in the setting of combining inhibitors of mitogen-activated protein (MAP)-extracellular signal-regulated kinase (ERK) kinase (MEK; MAP kinase kinase, MAP2K) with inhibitors of PI3 kinase (phosphatidylinositol 3-kinase, PIK3CA) or (2-7) BRAF (8)(9)(10), and these combinations are beginning to show efficacy in the clinic (11). A third approach to enhancing the efficacy of targeted therapy is to simultaneously target downstream proteins that protect tumor cells from apoptosis and thus increase overall cell killing (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Bcl-2/Bcl-xL Inhibition Increases the Efficacy of MEK Inhibition Alone and in Combination with PI3 Kinase Inhibition in Lung and Pancreatic Tumor Models

Tan¹,

Wong²,

Nannini³

et al. 2013

Molecular Cancer Therapeutics

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Although mitogen-activated protein (MAP)-extracellular signal-regulated kinase (ERK) kinase (MEK) inhibition is predicted to cause cell death by stabilization of the proapoptotic BH3-only protein BIM, the induction of apoptosis is often modest. To determine if addition of a Bcl-2 family inhibitor could increase the efficacy of a MEK inhibitor, we evaluated a panel of 53 non-small cell lung cancer and pancreatic cancer cell lines with the combination of navitoclax (ABT-263), a Bcl-2/Bcl-x L (BCL2/BCL2L1) antagonist, and a novel MAP kinase (MEK) inhibitor, G-963. The combination is synergistic in the majority of lines, with an enrichment of cell lines harboring KRAS mutations in the high synergy group. Cells exposed to G-963 arrest in G 1 and a small fraction undergo apoptosis. The addition of navitoclax to G-963 does not alter the kinetics of cell-cycle arrest, but greatly increases the percentage of cells that undergo apoptosis. The G-963/navitoclax combination was more effective than either single agent in the KRAS mutant H2122 xenograft model; BIM stabilization and PARP cleavage were observed in tumors, consistent with the mechanism of action observed in cell culture.

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Combinations of BRAF, MEK, and PI3K/mTOR Inhibitors Overcome Acquired Resistance to the BRAF Inhibitor GSK2118436 Dabrafenib, Mediated byNRASorMEKMutations

Cited by 319 publications

References 41 publications

Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo

Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo

“Combo” nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy

Bcl-2/Bcl-xL Inhibition Increases the Efficacy of MEK Inhibition Alone and in Combination with PI3 Kinase Inhibition in Lung and Pancreatic Tumor Models

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