BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis

Wilhelm, Scott M.; Carter, Christopher; Tang, LiYa; Wilkie, Dean; McNabola, Angela; Rong, Hong; Chen, Charles; Zhang, Xiaomei; Vincent, Patrick W.; McHugh, Mark; Cao, Yuntai; Shujath, Jaleel; Gawlak, Susan L.; Eveleigh, Deepa; Rowley, Bruce; Liu, Li; Adnane, Lila; Lynch, Mark; Auclair, Daniel; Taylor, Ian; Gedrich, Rich; Voznesensky, Andrei; Riedl, Bernd; Post, Leonard; Bollag, Gideon; Trail, Pamela A.

doi:10.1158/0008-5472.can-04-1443

Cited by 3,620 publications

(2,813 citation statements)

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“…Indeed, Antoun et al 12 reported that muscle loss was specifically exacerbated by sorafenib (Sor) treatment and described it as an adverse effect of the drug related to asthenia, fatigue, and physical disability. Sorafenib is a multikinase inhibitor that showed efficacy against a wide variety of tumours in pre‐clinical models13; it inhibits cell proliferation by targeting the Raf/MEK/ERK signalling pathways and exerts an anti‐angiogenic effect by inhibition of tumour angiogenesis through vascular endothelial growth factor receptor (VEGFR) and platelet‐derived growth factor receptor (PDGFR) 14, 15. It is already approved in humans for the treatment of advanced hepatocellular carcinoma16 and advanced renal cell carcinoma 17.…”

Section: Introductionmentioning

confidence: 99%

A multifactorial anti-cachectic approach for cancer cachexia in a rat model undergoing chemotherapy

Toledo

Penna

Oliva

et al. 2015

Journal of Cachexia, Sarcopenia and Muscle

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BackgroundThe effectiveness of drugs aimed at counteracting cancer cachexia is generally tested in pre‐clinical rodent models, where only the tumour‐induced alterations are taken into account, excluding the co‐presence of anti‐tumour molecules that could worsen the scenario and/or interfere with the treatment.MethodsThe aim of the present investigation has been to assess the efficacy of a multifactorial treatment, including formoterol and megestrol acetate, in cachectic tumour‐bearing rats (Yoshida AH‐130, a highly cachectic tumour) undergoing chemotherapy (sorafenib).ResultsTreatment of cachectic tumour‐bearing rats with sorafenib (90 mg/kg) causes an important decrease in tumour cell content due to both reduced cell proliferation and increased apoptosis. As a consequence, animal survival significantly improves, while cachexia occurrence persists. Multi‐factorial treatment using both formoterol and megestrol acetate is highly effective in preventing muscle wasting and has more powerful effects than the single formoterol administration. In addition, both physical activity and grip strength are significantly improved as compared with the untreated tumour‐bearing animals. The effects of the multi‐factorial treatment include increased food intake (likely due to megestrol acetate) and decreased protein degradation, as shown by the reduced expression of genes associated with both proteasome and calpain proteolytic systems.ConclusionsThe combination of the two drugs proved to be a promising strategy for treating cancer cachexia in a pre‐clinical setting that better resembles the human condition, thus providing a strong rationale for the use of such combination in clinical trials involving cachectic cancer patients.

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Section: Introductionmentioning

confidence: 99%

A multifactorial anti-cachectic approach for cancer cachexia in a rat model undergoing chemotherapy

Toledo

Penna

Oliva

et al. 2015

Journal of Cachexia, Sarcopenia and Muscle

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“…The Ras/Raf/mitogen-activated/extracellular-regulated kinase (MEK)/extracellular signal regulated kinase (ERK) pathway plays a pivotal role in control of proliferation and differentiation and, owing to its role as a gatekeeper of this pathway, Raf appears an attractive therapeutic target (O'Neill and Kolch, 2004;Wilhelm et al, 2004). The Raf-kinase family comprises the A-Raf, B-Raf and Raf-1 isoforms in vertebrates as well as D-Raf and LIN-45 in Drosophila and Caenorhabditis, respectively.…”

Section: Introductionmentioning

confidence: 99%

Functional analysis of the regulatory requirements of B-Raf and the B-RafV600E oncoprotein

et al. 2006

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The BRAF V600E mutation is found in approximately 6% of human cancers and mimics the phosphorylation of the kinase domain activation segment. In wild-type B-Raf (B-Raf wt ), activation segment phosphorylation is thought to cooperate with negative charges within the N-region for full activation. In contrast to Raf-1, the N-region of B-Raf is constitutively negatively charged owing to the presence of residues D447/D448 and the phosphorylation of S446. Therefore, it has been suggested that this hallmark predisposes B-Raf for oncogenic activation. In this study, we demonstrate that neutralizing mutations of these residues (in particular S446 and S447), or uncoupling of B-Raf from Ras-guanine 5 0 -triphosphate (GTP), strongly reduce the biological activity of B-Raf in a PC12 cell differentiation assay. We also confirm that S365 is a 14-3-3 binding site, and determine that mutation of this residue rescues the impaired biological activity of B-Raf proteins with a neutralized N-region, suggesting that the N-region opposes a 14-3-3-mediated transition into an inactive conformation. However, in the case of B-Raf V600E , although complete N-region neutralization resulted in a 2.5-fold reduction in kinase activity in vitro, this oncoprotein strongly induced PC12 differentiation or transformation and epithelial-mesenchymal transition of MCF-10A cells regardless of its N-region charge. Furthermore, the biological activity of B-Raf V600E was independent of its ability to bind Ras-GTP. Our analysis identifies important regulatory differences between B-Raf wt and B-Raf V600E and suggests that B-Raf V600E cannot be inhibited by strategies aimed at blocking S446 phosphorylation or Ras activation. Keywords: Ras; 14-3-3 proteins; b-Catenin; E-cadherin; mammary epithelial cells IntroductionThe Ras/Raf/mitogen-activated/extracellular-regulated kinase (MEK)/extracellular signal regulated kinase (ERK) pathway plays a pivotal role in control of proliferation and differentiation and, owing to its role as a gatekeeper of this pathway, Raf appears an attractive therapeutic target (O'Neill and Kolch, 2004;Wilhelm et al., 2004). The Raf-kinase family comprises the A-Raf, B-Raf and Raf-1 isoforms in vertebrates as well as D-Raf and LIN-45 in Drosophila and Caenorhabditis, respectively. B-Raf, the major ERK activator in vertebrates, is required for the maintenance of basal ERK activity and displays the most potent transforming activity (Papin et al., 1998;Brummer et al., 2002;Mercer and Pritchard, 2003). All isoforms share three highly conserved regions (CRs; Figure 1a): the N-terminal CR1 contains the Ras-guanine 5 0 -triphosphate (GTP)-binding domain (RBD), which initiates the interaction with Ras-GTP through a conserved arginine residue (R188 in B-Raf) that is required for the recruitment and activation of Raf at the plasma membrane. Consequently, mutation of this residue prevents Ras/Raf interaction and renders D-Raf, B-Raf and Raf-1 unresponsive to most extracellular signals (Hou et al., 1995;Marais et al., 1997;Brummer et al., 2002). The ...

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“…The orally administered targeted-agent sorafenib (Nexavar s , Bayer Pharmaceuticals Corporation, West Haven, CT, USA) was originally developed as an inhibitor of the RAF serine/threonine kinases (RAF-1, wild-type BRAF, V600E BRAF) (Wilhelm et al, 2004). However, results of in vitro studies have since shown that sorafenib is a potent multikinase inhibitor, which also targets receptor tyrosine kinases associated with tumour angiogenesis (VEGFR-2, VEGFR-3, PDGFR-b) and tumour progression (c-KIT, FLT-3) (Wilhelm et al, 2004).…”

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confidence: 99%

“…However, results of in vitro studies have since shown that sorafenib is a potent multikinase inhibitor, which also targets receptor tyrosine kinases associated with tumour angiogenesis (VEGFR-2, VEGFR-3, PDGFR-b) and tumour progression (c-KIT, FLT-3) (Wilhelm et al, 2004). Sorafenib has also been shown to inhibit the growth of several human tumour xenograft models by targeting tumour cell proliferation and/or endothelial cellmediated tumour angiogenesis (Wilhelm et al, 2004).…”

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confidence: 99%

Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis

et al. 2006

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The effects of sorafenib -an oral multikinase inhibitor targeting the tumour and tumour vasculature -were evaluated in patients with advanced melanoma enrolled in a large multidisease Phase II randomised discontinuation trial (RDT). Enrolled patients received a 12-week run-in of sorafenib 400 mg twice daily (b.i.d.). Patients with changes in bi-dimensional tumour measurements o25% from baseline were then randomised to sorafenib or placebo for a further 12 weeks (ie to week 24). Patients with X25% tumour shrinkage after the run-in continued on open-label sorafenib, whereas those with X25% tumour growth discontinued treatment. This analysis focussed on secondary RDT end points: changes in bi-dimensional tumour measurements from baseline after 12 weeks and overall tumour responses (WHO criteria) at week 24, progression-free survival (PFS), safety and biomarkers (BRAF, KRAS and NRAS mutational status). Of 37 melanoma patients treated during the run-in phase, 34 were evaluable for response: one had X25% tumour shrinkage and remained on open-label sorafenib; six (16%) had o25% tumour growth and were randomised (placebo, n ¼ 3; sorafenib, n ¼ 3); and 27 had X25% tumour growth and discontinued. All three randomised sorafenib patients progressed by week 24; one remained on sorafenib for symptomatic relief. All three placebo patients progressed by week-24 and were re-started on sorafenib; one experienced disease re-stabilisation. Overall, the confirmed best responses for each of the 37 melanoma patients who received sorafenib were 19% stable disease (SD) (ie n ¼ 1 open-label; n ¼ 6 randomised), 62% (n ¼ 23) progressive disease (PD) and 19% (n ¼ 7) unevaluable. The overall median PFS was 11 weeks. The six randomised patients with SD had overall PFS values ranging from 16 to 34 weeks. The most common drug-related adverse events were dermatological (eg rash/desquamation, 51%; hand-foot skin reaction, 35%). There was no relationship between V600E BRAF status and disease stability. DNA was extracted from the biopsies of 17/22 patients. Six had V600E-positive tumours (n ¼ 4 had PD; n ¼ 1 had SD; n ¼ 1 unevaluable for response), and 11 had tumours containing wild-type BRAF (n ¼ 9 PD; n ¼ 1 SD; n ¼ 1 unevaluable for response). In conclusion, sorafenib is well tolerated but has little or no antitumour activity in advanced melanoma patients as a single agent at the dose evaluated (400 mg b.i.d.). Ongoing trials in advanced melanoma are evaluating sorafenib combination therapies.

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BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis

Cited by 3,620 publications

References 27 publications

A multifactorial anti-cachectic approach for cancer cachexia in a rat model undergoing chemotherapy

A multifactorial anti-cachectic approach for cancer cachexia in a rat model undergoing chemotherapy

Functional analysis of the regulatory requirements of B-Raf and the B-RafV600E oncoprotein

Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis

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