Enhanced Inhibition of ERK Signaling by a Novel Allosteric MEK Inhibitor, CH5126766, That Suppresses Feedback Reactivation of RAF Activity

Ishii, Nobuya; Harada, Naoki; Joseph, Eric W.; Ohara, Kazuhiro; Miura, Takaaki; Sakamoto, Hiroshi; Matsuda, Yutaka; Tomii, Yasushi; Tachibana-Kondo, Yukako; Iikura, Hitoshi; Aoki, Toshihiro; Shimma, Nobuo; Arisawa, Mikio; Sowa, Yoshihiro; Poulikakos, Poulikos I.; Rosen, Neal; Aoki, Yuko; Sakai, Toshiyuki

doi:10.1158/0008-5472.can-12-3937

Cited by 127 publications

(125 citation statements)

References 30 publications

(39 reference statements)

Supporting

Mentioning

118

Contrasting

Unclassified

Order By: Relevance

“…CH5126766, a RAF-MEK inhibitor, showed superior antitumor efficacy in comparison to the MEK inhibitor alone (17). Although both inhibitors suppressed phospho-ERK in tumors, CH5126766 more strongly suppressed downstream signaling targets such as DUSPs and SPREADs (17). In FGFR-altered cancer cells, DUSP6 was more significantly suppressed by CH5183284/Debio 1347 than by CH5126766 (Fig.…”

Section: Discussionmentioning

confidence: 94%

“…Conversely, cancer cells that were not phospho-S6-suppressed were resistant to BYL719, although AKT phosphorylation was inhibited (46). CH5126766, a RAF-MEK inhibitor, showed superior antitumor efficacy in comparison to the MEK inhibitor alone (17). Although both inhibitors suppressed phospho-ERK in tumors, CH5126766 more strongly suppressed downstream signaling targets such as DUSPs and SPREADs (17).…”

Section: Discussionmentioning

confidence: 99%

“…CH5183284/Debio 1347 (FGFR inhibitor), CH4987655 (MEK inhibitor), CH5126766 (RAF-MEK inhibitor), and CH5132799 (PI3K inhibitor) were synthesized at Chugai Pharmaceutical Co. Ltd., as previously described (7,(16)(17)(18). AZD4547 was synthesized at Chugai Pharmaceutical Co. Ltd. (patent publication WO2008075068).…”

Section: Reagents and Cell Linesmentioning

confidence: 99%

See 2 more Smart Citations

ERK Signal Suppression and Sensitivity to CH5183284/Debio 1347, a Selective FGFR Inhibitor

Nakanishi¹,

Mizuno²,

Sase³

et al. 2015

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

Drugs that target specific gene alterations have proven beneficial in the treatment of cancer. Because cancer cells have multiple resistance mechanisms, it is important to understand the downstream pathways of the target genes and monitor the pharmacodynamic markers associated with therapeutic efficacy. We performed a transcriptome analysis to characterize the response of various cancer cell lines to a selective fibroblast growth factor receptor (FGFR) inhibitor (CH5183284/Debio 1347), a mitogen-activated protein kinase kinase (MEK) inhibitor, or a phosphoinositide 3-kinase (PI3K) inhibitor. FGFR and MEK inhibition produced similar expression patterns, and the extracellular signal-regulated kinase (ERK) gene signature was altered in several FGFR inhibitor-sensitive cell lines. Consistent with these findings, CH5183284/Debio 1347 suppressed phospho-ERK in every tested FGFR inhibitor-sensitive cell line. Because the mitogen-activated protein kinase (MAPK) pathway functions downstream of FGFR, we searched for a pharmacodynamic marker of FGFR inhibitor efficacy in a collection of cell lines with the ERK signature and identified dual-specificity phosphatase 6 (DUSP6) as a candidate marker. Although a MEK inhibitor suppressed the MAPK pathway, most FGFR inhibitor-sensitive cell lines are insensitive to MEK inhibitors and we found potent feedback activation of several pathways via FGFR. We therefore suggest that FGFR inhibitors exert their effect by suppressing ERK signaling without feedback activation. In addition, DUSP6 may be a pharmacodynamic marker of FGFR inhibitor efficacy in FGFR-addicted cancers.

show abstract

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

ERK Signal Suppression and Sensitivity to CH5183284/Debio 1347, a Selective FGFR Inhibitor

Nakanishi¹,

Mizuno²,

Sase³

et al. 2015

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

show abstract

“…By contrast, CKI evoked a more sustained p-ERK inhibition, which was associated with greater restoration of NIS expression (Figure 1, D and E). CKI was administered once per day and AZD6244 on a 12-hour schedule throughout the experiment, consistent with their known pharmacokinetic properties (12,15). The more effective blockade of the pathway by CKI also resulted in greater and more durable reduction of tumor size as compared with AZD6244 (Supplemental Figure 2).…”

Section: Kinetics Of Nis Activity In Brafmentioning

confidence: 97%

“…CH5126766 (CKI) is an allosteric MEK inhibitor that, on binding to the protein, causes it to adopt a conformation in which it cannot be phosphorylated by RAF. The drug-bound MEK functions as a dominant-negative inhibitor of WT and activated mutant RAF kinases and reduces feedback reactivation of ERK signaling (12,13).…”

Section: Introductionmentioning

confidence: 99%

Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine

Nagarajah¹,

Le²,

Knauf³

et al. 2016

Journal of Clinical Investigation

Self Cite

110

View full text Add to dashboard Cite

Pathway profiling of a novel SRC inhibitor, AZD0424, in combination with MEK inhibitors for cancer treatment

et al. 2021

View full text Add to dashboard Cite

A more comprehensive understanding of how cells respond to drug intervention, the likely immediate signalling responses and how resistance may develop within different microenvironments will help inform treatment regimes. The nonreceptor tyrosine kinase SRC regulates many cellular signalling processes, and pharmacological inhibition has long been a target of cancer drug discovery projects. Here, we describe the in vitro and in vivo characterisation of the small-molecule SRC inhibitor AZD0424. We show that AZD0424 potently inhibits the phosphorylation of tyrosine-419 of SRC (IC50 ~100 nM) in many cancer cell lines; however, inhibition of cell viability, via a G1 cell cycle arrest, was observed only in a subset of cancer cell lines in the low (on target) micromolar range. We profiled the changes in intracellular pathway signalling in cancer cells following exposure to AZD0424 and other targeted therapies using reverse-phase protein array (RPPA) analysis. We demonstrate that SRC is activated in response to treatment of KRAS-mutant colorectal cell lines with MEK inhibitors (trametinib or AZD6244) and that AZD0424 abrogates this. Cell lines treated with trametinib or AZD6244 in combination with AZD0424 had reduced EGFR, FAK and SRC compensatory activation, and cell viability was synergistically inhibited. In vivo, trametinib treatment of mice-bearing HCT116 tumours increased phosphorylation of SRC on Tyr419, and, when combined with AZD0424, inhibition of tumour growth was greater than with trametinib alone. We also demonstrate that drug-induced resistance to trametinib is not re-sensitised by AZD0424 treatment in vitro, likely as a result of multiple compensatory signalling mechanisms; however, inhibition of SRC remains an effective way to block invasion of trametinib-resistant tumour cells. These data imply that SRC inhibition may offer a useful addition to MEK inhibitor combination strategies.

show abstract

Enhanced Inhibition of ERK Signaling by a Novel Allosteric MEK Inhibitor, CH5126766, That Suppresses Feedback Reactivation of RAF Activity

Cited by 127 publications

References 30 publications

ERK Signal Suppression and Sensitivity to CH5183284/Debio 1347, a Selective FGFR Inhibitor

ERK Signal Suppression and Sensitivity to CH5183284/Debio 1347, a Selective FGFR Inhibitor

Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine

Pathway profiling of a novel SRC inhibitor, AZD0424, in combination with MEK inhibitors for cancer treatment

Contact Info

Product

Resources

About