Relief of Profound Feedback Inhibition of Mitogenic Signaling by RAF Inhibitors Attenuates Their Activity in BRAFV600E Melanomas

Lito, Piro; Pratilas, Christine A.; Joseph, Eric W.; Tadi, Madhavi; Halilovic, Ensar; Zubrowski, Matthew; Huang, Alan; Wong, Wai Lin; Callahan, Margaret K.; Merghoub, Taha; Wolchok, Jedd D.; Stanchina, Elisa de; Chandarlapaty, Sarat; Poulikakos, Poulikos I.; Fagin, James A.; Rosen, Neal

doi:10.1016/j.ccr.2012.10.009

Cited by 484 publications

(527 citation statements)

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“…These findings are in concordance with recent reports that BRAF V600E melanoma cells become dependent on reactivation of ERK signaling despite ongoing inhibition of mutant BRAF (22,23). We therefore evaluated the antiproliferative activity of TAK-733 in A375-VR cells in both the presence and absence of the BRAF inhibitor (Fig.…”

Section: Inhibition Of Braf V600e Enhances the Activity Of Mek Inhibisupporting

confidence: 78%

“…1, 6, 28), with the vast majority leading to reactivation of ERK activity despite the presence of the inhibitor. For example, Lito and colleagues recently showed that an elevated state of ERK-dependent feedback potently suppresses ligand-dependent signaling by growth factors and upstream RAS activity in BRAF V600E -driven melanoma cells (22). Treatment with vemurafenib, which inhibits BRAF monomers but not homo-or heterodimers, potently relieves this ERKdependent feedback and creates a permissible environment for reactivation of ligand-dependent signaling.…”

Section: Discussionmentioning

confidence: 99%

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Overcoming Acquired BRAF Inhibitor Resistance in Melanoma via Targeted Inhibition of Hsp90 with Ganetespib

Acquaviva

Smith

Jimenez

et al. 2014

Molecular Cancer Therapeutics

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Activating BRAF kinase mutations serve as oncogenic drivers in over half of all melanomas, a feature that has been exploited in the development of new molecularly targeted approaches to treat this disease. Selective BRAF V600E inhibitors, such as vemurafenib, typically induce initial, profound tumor regressions within this group of patients; however, durable responses have been hampered by the emergence of drug resistance. Here, we examined the activity of ganetespib, a small-molecule inhibitor of Hsp90, in melanoma lines harboring the BRAF V600E mutation. Ganetespib exposure resulted in the loss of mutant BRAF expression and depletion of mitogen-activated protein kinase and AKT signaling, resulting in greater in vitro potency and antitumor efficacy compared with targeted BRAF and MAP-ERK kinase (MEK) inhibitors. Dual targeting of Hsp90 and BRAF V600E provided combinatorial benefit in vemurafenibsensitive melanoma cells in vitro and in vivo. Importantly, ganetespib overcame mechanisms of intrinsic and acquired resistance to vemurafenib, the latter of which was characterized by reactivation of extracellular signal-regulated kinase (ERK) signaling. Continued suppression of BRAF V600E by vemurafenib potentiated sensitivity to MEK inhibitors after acquired resistance had been established. Ganetespib treatment reduced, but not abolished, elevations in steady-state ERK activity. Profiling studies revealed that the addition of a MEK inhibitor could completely abrogate ERK reactivation in the resistant phenotype, with ganetespib displaying superior combinatorial activity over vemurafenib. Moreover, ganetespib plus the MEK inhibitor TAK-733 induced tumor regressions in vemurafenib-resistant xenografts. Overall these data highlight the potential of ganetespib as a single-agent or combination treatment in BRAF V600E -driven melanoma, particularly as a strategy to overcome acquired resistance to selective BRAF inhibitors. Mol Cancer Ther; 13(2); 353-63. Ó2014 AACR.

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Section: Inhibition Of Braf V600e Enhances the Activity Of Mek Inhibisupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Overcoming Acquired BRAF Inhibitor Resistance in Melanoma via Targeted Inhibition of Hsp90 with Ganetespib

Acquaviva

Smith

Jimenez

et al. 2014

Molecular Cancer Therapeutics

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“…Treatment of BRAF‐V600E tumors with small molecule inhibitors often leads to drug resistance and tumor regrowth, a behavior characterized by a transient drop in phosphorylated ERK (pERK) followed by a return in pERK levels. By explicitly formalizing different word models representing alternative mechanisms (Poulikakos et al , 2010; Lito et al , 2012; Yao et al , 2015), INDRA revealed that both pERK‐mediated feedback and BRAF dimerization were necessary for the observed pERK rebound and adaptive behavior. At minimum, they predicted, an accurate model of BRAF‐V600E drug resistance should contain both of these features.…”

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confidence: 99%

Natural language processing: put your model where your mouth is

Haggerty

Purvis

2017

Molecular Systems Biology

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Molecular mechanisms are often described using “word models”—phrases intended to capture the interactions in a biological process. In their recent work, Sorger and colleagues (Gyori et al, 2017) provide a framework for converting word models into computational structures that can be simulated and compared to experimental data. By codifying word‐based descriptions of molecular phenomena, scientific communities can better evaluate, compare, and share mechanistic insights.

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“…The effects of vemurafenib on ERK activity in BRAF-mutant cells can also be attenuated by the relief of ERK-dependent negative feedback that in untreated cells suppresses RTK signaling upstream of the mutant oncogene. This adaptive response to RAF inhibition occurs rapidly (within hours), limits the effectiveness of the drug, and may facilitate the selection of drug-resistant clones ( 8,9 ).…”

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confidence: 99%

“…By inhibiting RAF dimer-dependent ERK activation, cotreatment with a MEK inhibitor results in more potent and durable suppression of ERK signaling and greater antitumor effects in preclinical models ( 8 ). Combination therapy may also delay or prevent the emergence of preexisting drug-resistant clones, thus extending the duration of response.…”

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confidence: 99%

ERK Pathway Inhibitors: How Low Should We Go?

2013

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Summary:Resistance to RAF inhibitors is generally accompanied by reactivation of extracellular signal-regulated kinase (ERK) signaling. SCH772984, a selective, ATP-competitive inhibitor of ERK1 and ERK2, is effective in BRAF-mutant models in which resistance is the result of ERK reactivation. SCH772984 may also have a role in the treatment of tumors in which ERK is dysregulated by mutant RAS, NF1, or activated receptor tyrosine kinases, settings in which current RAF inhibitors are ineffective. Cancer Discov; 3(7); 719-21. ©2013 AACR.See related article by Morris et al., p. 742 (11).The mitogen-activated protein kinase (MAPK) pathway is a key regulator of cellular proliferation and survival. The pathway is a three-tiered kinase cascade consisting of the RAF, MEK (MAP-ERK kinase), and ERK (extracellular signal-regulated kinase) kinases ( Fig. 1 ). In normal cells, RAS activates RAF kinases, in part by promoting the formation of RAF dimers. Active RAF in turn phosphorylates and activates MEK1 and MEK2, which upon activation phosphorylate ERK1 and ERK2. ERK exerts its cellular effects by regulating the activity and expression of multiple nuclear transcription factors and cytosolic proteins. Somatic alterations in MAPK pathway components that deregulate the pathway are highly prevalent in human cancer. ERK pathway activation in tumors can result from mutations in all three RAS genes ( KRAS , NRAS , HRAS ), mutations in BRAF and MAP2K1 (MEK1), loss of NF1 function due to mutation, deletion, and/or promoter methylation, and activation of RAS by cell surface receptors.Intensive efforts have been directed toward the identifi cation and preclinical and clinical development of selective inhibitors of MAPK signaling for use as anticancer therapies. Clinically useful, direct inhibitors of oncogenic RAS have yet to be identifi ed. One alternative approach is to target the downstream effector kinases responsible for RAS-mediated transformation. Great success has been achieved with the use of selective inhibitors of RAF (vemurafenib and dabrafenib). Vemurafenib is U.S. Food and Drug Administrationapproved for patients with BRAF-mutant melanoma and has shown unprecedented clinical activity in this setting ( 1 ). Vemurafenib, however, inhibits ERK pathway activity only in tumors that harbor mutations in BRAF and is ineffective in cancers in which ERK activity is driven by RAS mutations or receptor tyrosine kinase (RTK) activation ( 2 ). In fact, ATPcompetitive RAF inhibitors enhance ERK signaling in BRAFwild-type cells. The mechanistic basis for this "paradoxical" activation of ERK signaling, namely, drug-mediated transactivation of RAF dimers ( 3 ), has implications for the development of novel therapeutic strategies seeking to address both intrinsic and acquired resistance to RAF inhibitors.Vemurafenib and dabrafenib induce tumor regression in most patients with BRAF V600E melanoma, but complete remissions are rare and responses are often temporary ( 1 ). Several mechanisms of resistance to vemurafenib have been identifi ed in ...

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Relief of Profound Feedback Inhibition of Mitogenic Signaling by RAF Inhibitors Attenuates Their Activity in BRAFV600E Melanomas

Cited by 484 publications

References 42 publications

Overcoming Acquired BRAF Inhibitor Resistance in Melanoma via Targeted Inhibition of Hsp90 with Ganetespib

Overcoming Acquired BRAF Inhibitor Resistance in Melanoma via Targeted Inhibition of Hsp90 with Ganetespib

Natural language processing: put your model where your mouth is

ERK Pathway Inhibitors: How Low Should We Go?

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