SCH772984

Therapeutic options for managing Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest types of aggressive malignancies, are limited and disappointing. Mechanistically, we anticipate that the GEM efficacy was increased as ERKi blocks desmoplasia by impairing the production of desmoplastic regulatory factors in PDAC cells and KPC mouse tumors. Therefore, 2nd generation ERKi (SCH 772984)-iRGD-pHNPs are vital for the cellular response to GEM and denote a promising therapeutic target in PDAC with mutant K-RAS.

RAE1 promotes GC cell migration and invasion through the ERK/MAPK pathway and is a potential therapeutic target for GC therapy.

Furthermore, PP4R1 enhanced the suppressive effects of the ERK inhibitor SCH772984 on GBC. In conclusion, our data showed that PP4R1 is a promising biomarker associated with GBC and confirmed that PP4R1 regulates PKM2-mediated tumor glycolysis, which provides a metabolic growth advantage to GBC cells, thereby promoting GBC tumor growth and metastasis.

Overall, our findings revealed that the Collagen I-induced loss of OSBPL2 aggravates CRC progression through VCAN-mediated ERK signaling and the PARP1/ZEB1 axis. This demonstrates that SCH772984 and AG14361 are reciprocally connective therapies for OSBPL2 CRC, which could contribute to further development of targeted CRC treatment.

We identified a necroptosis signature in LUSC that can predict prognosis and identify patients who can benefit from targeted therapies.

In NSCLC, DHX38 functions as a tumor promoter. DHX38 modulates G3BP1 expression, leading to the activation of the MAPK signaling pathway, thus promoting tumor cell proliferation, metastasis, and the progression of epithelial-mesenchymal transition (EMT) in non-small cell lung cancer.

In the present study, we first found that PCD-related gene expression patterns were correlated with clinical features of CESC patients, which predicts the feasibility of subsequent mining of prognostic features based on these genes. The five-PCD-associated-gene prognostic model showed good assessment ability in predicting patient prognosis, immune response and drug-sensitive response, and provided guidance for the elucidation of the mechanism by which PCD affects CESC, as well as for the clinical targeting of drugs.

Our results demonstrated that SETD2 inhibits the RAS/ERK signaling pathway by facilitating the transcription of DUSP7 in SMAD4-deficient CRC, which could provide a potential therapeutic target for the treatment of advanced CRC.

In conclusion, our results demonstrated that IL-33 plays a protective role in the progression of atherosclerosis by inhibiting cell adhesion via the ERK1/2-IRF1-VCAM-1 pathway. This study may provide a potential therapeutic way to prevent the development of atherosclerosis.

MTT, Transwell, and three-dimensional cell culture assays were used to detect the survival, migration, invasion, and tube formation of U87MG cells that overexpressed Mig-7 were treated with the MAPK signaling pathway inhibitors (SP600125, SCH772984, and SB202190). These effects of Mig-7 overexpression were reversed by MAPK pathway inhibitors. Overall, these results suggest that Mig-7 may be a novel biomarker and potential therapeutic target for glioma, with the MAPK pathway playing a key role in the corresponding Mig-7 mechanism of action.

Sensitivity to Trametinib (MEK1/2 inhibitor) and SCH772984 (ERK inhibitor) were significantly associated with higher TMB values (p < 0.05). Ruxolitinib demonstrated higher effectiveness in IL-6 dependent myeloma cell lines (p < 0.003). Presence of DDR protein (tp53, ATR, ATM) mutations were associated with higher Drug Sensitivity scores in Nutlin-3a, UMI77, and Doxorubicin (p < 0.05)... Our study underscores the significance of establishing ex vivo drug response panels in addition to NGS and immunochemistry data to advance precision medicine approaches in multiple myeloma. Addressing potential vulnerabilities created by common mechanisms of resistance may be more widely applicable than targeting rare activating mutations in RRMM. Therefore, by leveraging targeted therapy, patients can achieve favourable treatment responses, thus enabling them to gain access to subsequent immunotherapy options and maximize their therapeutic benefits.

Colorectal cancer cells may induce the formation of colorectal CAFs by activating the ERK pathway in the fibroblasts.

These data reflect the complexity of cisplatin resistance in cell models and emphasize NHC-Au(I)-complexes as prospective cytotoxic agents for further investigations in that respect.

However, in combination with the Mcl-1 inhibitor S63845, the effects of vemurafenib were strongly enhanced in BRAF-mutated cell lines, and the effects of SCH772984 were enhanced in both BRAF-mutated and BRAF-WT cells. The combination finally resulted in downregulation of antiapoptotic Bcl-2 and enhanced expression of the proapoptotic Noxa. In conclusion, combined inhibition of ERK and Mcl-1 revealed an impressive efficacy both in BRAF-mutated and WT melanoma cells, and may thus represent a new strategy for overcoming drug resistance.

To understand the pathway through which the G13D mutation induced the effects, we studied both RAS/ERK and PI3K/Akt pathways using specific inhibitors SCH772984 and BEZ235. Inhibition of this mutation reverses the process. Therefore, care needs be taken when employing targeted therapies to K-Ras mutations in clinics.

Here, we report a FOXD1-dependent RalA-ANXA2-Src complex that promotes CTC formation via activating ERK1/2 signal in BC. FOXD1 may serve as a prognostic factor in evaluation of BC metastasis risks. This signaling cascade is druggable and effective for overcoming CTC formation from the early stages of BC.

Moreover, the mechanistic study indicated that AHSA1 recruited ERK1/2 and promoted the phosphorylation and inactivation of CALD1, while ERK1/2 phosphorylation inhibitor SCH772984 reversed the role of AHSA1 in the proliferation and EMT of HCC...We also illustrated a new molecular mechanism associated with AHSA1 in HCC that was independent of HSP90 and MEK1/2. In summary, AHSA1 may play an oncogenic role in HCC by regulating ERK/CALD1 axis and may serve as a novel therapeutic target for HCC.

Using ERK1/2 and downstream kinase ELK1 reporter cell lines of lung cancer (H1299; NRAS), colon cancer (HCT-116; KRAS), neuroblastoma (SH-SY5Y), and leukemia (U937), we examined the relationship between ERK inhibition and drug-induced toxicity for five ERK inhibitors: SCH772984, ravoxertinib, LY3214996, ulixertinib, and VX-11e, as well as one MEK inhibitor, PD0325901. We also showed that cells that became resistant to the MEK1/2 inhibitor PD0325901 due to ERK1/2 reactivation remained sensitive to ERK1/2 inhibitor ulixertinib. Our data indicate that correlation of ERK inhibition with drug-induced toxicity in multiple cell lines may help to find more selective and effective ERK1/2 inhibitors.

Finally, the cancer promotion phenomenon caused by BTN3A3 knockdown can be improved by using ERK1/2 inhibitor SCH772984. To sum up, BTN3A3 interacts with FGF2, which inhibits FGF2/ERK1/2 axis and ultimately inhibits the proliferation, migration and invasion of ovarian cancer cells. Our results suggest that BTN3A3 may be a prognostic marker and a potential therapeutic target for ovarian cancer.

In this study, the efficacy of combined PI3K/mTOR (BEZ235) and ERK inhibition (SCH772984) was investigated in four human ovarian cancer cell lines, grown as monolayer and three-dimensional cell aggregates. These findings suggest that combined PI3K/mTOR and ERK inhibition could be a useful strategy for overcoming treatment resistance in ovarian cancer and warrants further preclinical investigation. Additionally, in some cell lines the use of different three-dimensional models can influence cell line sensitivity to PI3K/mTOR and RAS/RAF/MEK/ERK pathway inhibitors.

LAGE3 enhanced the malignant phenotypes of HCC by promoting the JNK and ERK signaling pathway.

Additionally, administration of ERK1/2 blocker SCH772984 attenuated the proliferative and migratory phenotype induced by DCLK1-S. In conclusion, these findings suggest that DCLK1-S may be a key molecule in MAPK/ERK/MMP2 pathway-mediated progression of ESCC, and that it has potential as a biomarker or therapeutic target to improve outcomes in ESCC patients. Implications: DCLK1-S induces ESCC progression by activating the MAPK/ERK/MMP2 axis and may serve as a prognostic biomarker or therapeutic target for ESCC patients.

Interestingly, PLAT/tPA decreases autophagy to mediate neuroprotection by modulating the PI3K-AKT-MTOR pathways both in vitro and in vivo. We identified IGF1R (insulin-like growth factor I receptor; a tyrosine kinase receptor) as the effective receptor and showed in vitro, in vivo and in human stroke patients and that PLAT/tPA is able to degrade IGFBP3 (insulin-like growth factor binding protein 3) to increase IGF1 (insulin-like growth factor 1) bioavailability and thus IGF1R activation.Abbreviations: AKT/protein kinase B: thymoma viral proto-oncogene 1; EGFR: epidermal growth factor receptor; Hx: hypoxia; IGF1: insulin-like growth factor 1; IGF1R: insulin-like growth factor I receptor; IGFBP3: insulin-like growth factor binding protein 3; Ka: Kainate; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK/ERK: mitogen-activated protein kinase; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; OGD: oxygen and glucose deprivation; OGD: oxygen and glucose deprivation + reoxygentation; PepA: pepstatin A1; PI3K: phosphoinositide 3-kinase; PLAT/tPA: plasminogen activator, tissue; PPP: picropodophyllin; SCH77: SCH772984; ULK1: unc-51 like kinase 1; Wort: wortmannin.

In addition, the combination of ERK1/2 inhibitor SCH772984 and cyclin-dependent kinase (CDK)4/6 inhibitor palbociclib showed a remarkable inhibitory effect on tumor growth in vivo. More importantly, insulin and OA were confirmed to synergistically promote the deterioration of CRC in vitro and in vivo via ERK1/2/c-Myc/cyclin D1 pathway. Our findings may shed light on CRC treatment among the T2D population.

Moreover, we indicated that the ERK/Fos signaling pathway was intensively inactivated after overexpression of miR-506 and PENK both in vitro and in vivo, which was further validated by the ERK1/2-specific inhibitor SCH772984. In conclusion, this study demonstrates that miR-506-loaded GNs have great potential in anti-TNBC aggressiveness therapy.

The present study aims to analyze the association between the molecular characteristics which analyzed by next-generation sequencing (NGS) and sensitivity to the ERK inhibitor (i.e., SCH772984) in PDO derived from CRC specimens...The results of this study suggested that the molecular status of the clinical specimens are likely to represent the sensitivity in the PDOs but is not necessarily absolutely overlapping. PDO might be able to complement the limitations of the gene panel and have the potential to provide a novel precision medicine.

Here, we examined the effect of combined BRAF inhibition (dabrafenib) and ERK1/2 inhibition (SCH772984) on the growth and survival of a panel of BRAF-mutant thyroid cancer cell lines using in vitro and in vivo approaches. Finally, combined inhibition of BRAF and ERK1/2 results in enhanced inhibition of tumor growth in an anaplastic thyroid cancer in vivo model. These results provide key rationale to pursue combined BRAF and ERK1/2 inhibition as an alternative therapeutic strategy for BRAF-mutant advanced thyroid cancer patients.

MEK and ERK inhibition causes antiproliferative effects in human NET cell lines in vitro. The combination of the MEK inhibitor trametinib (TMT212) with the CDK4/6 inhibitor ribociclib (LEE011) causes additive antiproliferative effects. Future preclinical and clinical studies of MEK inhibition in NETs should be performed.

Furthermore, silencing the ERK pathway by SCH772984 led to the inhibition of Rap2B-mediated proliferation, migration and the reduction of MMP2 and MMP9 expression...These results demonstrated that Rap2B may participate in the processes of glioma cell proliferation and migration through enhancing MMP2 and MMP9 expression via the ERK pathway. Thus, Rap2B could potentially be used as a promising therapeutic target and prognostic biomarker in glioma.

In KRAS-mutant Pa16C pancreatic cancer cells, while KRAS knockdown resulted in over 8,000 differentially methylated (DM) CpGs, treatment with the ERK1/2-selective inhibitor SCH772984 showed less than 40 DM CpGs, suggesting that ERK is not a broadly active driver of KRAS-associated DNA methylation...Taken all together, KRAS-mediated DNA methylation are stochastic and independent of canonical downstream effector signaling. These epigenetically altered genes associated with KRAS expression could represent potential therapeutic targets in KRAS-driven cancer.

Moreover, SCH772984 and SP600125, ERK and JNK inhibitors, respectively, could partially abolish NCTD-induced apoptosis and G2/M phase cell cycle arrest. Collectively, these findings suggest that NCTD might activate JNK and ERK signaling pathways, consequently inducing apoptosis and G2/M arrest through the modulation of related proteins. This study provided evidence that NCTD is a promising therapeutic drug for the treatment of RCC.

The present study suggested that downregulation of lncRNA CCHE1 could inhibit cell proliferation, migration and invasion by suppressing MEK/ERK/c-MYC pathway in nasopharyngeal carcinoma.

PC-9, PC-9/GR and H1975 cells were treated with JB, LY294002, SCH772984, gefitinib alone or in combination. Moreover, JB could synergize with gefitinib to induce apoptosis in PC-9, PC-9/GR and H1975 cells. These data indicated that JB could be a potential therapeutic agent for NSCLC patients harboring EGFR mutations as well as those under gefitinib resistance.

Inhibition of the ERK1/2 pathway by SCH772984 reduces CSF-1R-induced migration, invasion, and lung metastasis of glioma cells, thus establishing a role of the ERK1/2 signaling pathway in mediating the CSF-1R effect. In summary, our results suggest that CSF-1R overexpression in gliomas contributes to the malignant behaviors of cancer cells.

We showed that both MAPK and IGF1R pathway inhibition, using the ERK inhibitor SCH772984 and the IGF1R inhibitor BMS-754807, respectively, restored BRAFi sensitivity in melanoma cells lacking HAT1. Collectively, we show that the loss of HAT1 expression confers acquired BRAFi resistance by activating the MAPK signaling pathway via IGF1R.

Importantly, these effects of β-hCG were mediated by activation of the ERK/MMP2 signaling pathway, independently of luteinizing hormone/chorionic gonadotropin receptor (LHCGR) presence, and inhibition the pathway with the p-ERK1/2 inhibitor SCH772984 significantly impaired the tumor-promoting effects induced by β-hCG. Collectively, these data provide new insight into the roles and mechanisms of β-hCG in regulating EOC metastasis through ERK/MMP2 signaling pathway and may become a new target for therapeutic intervention.

The best treatments include the combination of B-Raf and MEK inhibitors (dabrafenib and trametinib, encorafenib and binimetinib, vemurafenib and cobimetanib)...Ulixertinib, MK-8353, and GDC-0994 are orally effective, potent, and specific inhibitors of ERK1/2 that are in early clinical trials for the treatment of various advanced/metastatic solid tumors...The decrease in RSK phosphorylation appears to be a result of ERK inhibition and the decrease in ERK1/2 phosphorylation is related to the inability of MEK to catalyze the phosphorylation of the ERK-MK-8353 complex; these decreases characterize the ERK dual mechanism inhibition paradigm. Additional work will be required to determine whether ERK inhibitors will be successful in the clinic and are able to forestall the development of drug resistance of the MAP kinase pathway.

To anticipate possible resistance to ERK inhibitors (ERKi), we used SCH772984 (SCH) as a model ERKi to characterize resistance mechanisms in two BRAF V600E melanoma cell lines. The ERKi-resistant cells were also resistant to vemurafenib (VMF), trametinib (TMT), and combined treatment with either VMF and SCH or TMT and SCH...Inhibition of IGF1R with linsitinib blocked Erk5 activation in SCH-resistant cells and decreased their growth in 3D spheroid growth assays as well as in NOD scid gamma (NSG) mice...In addition, we found that the decreased Erk1/2 activation in SCH-resistant cells involved reduced expression and function of TGF-alpha. These data reveal an escape signaling route that melanoma cells use to bypass Erk1/2 blockade during targeted melanoma treatment and offer several possible targets whose disruption may circumvent resistance.

Furthermore, inhibition of FLT3-ITD by quizartinib or gilteritinib, but not that of BCR/ABL by imatinib, prominently inhibited RSK1 and RSK2 NTKDs, as examined by the activation-specific phosphorylation in their T-loop sites, associated with inhibition of the MEK/Erk pathway and PDK1 in MV4-11...On the other hand, inhibition of RSK or Erk by LJH685 or SCH772984, respectively, increased the expression level of BimEL in the S65-phosphorylated or unphosphorylated form, respectively, which is consistent with the idea that RSK phosphorylates BimEL after its phosphorylation on S65 by Erk to induce proteasomal degradation of this potent pro-apoptotic protein...LJH685 or RSK1 knockout reduced viable cell numbers of MV4-11 as well as FLT3-ITD-positive primary AML cells synergistically with the PIM inhibitor AZD-1208 or the PI3K inhibitor GDC-0941 at least partly by inducing apoptosis, which was prevented by overexpression of Bcl-xL or Mcl-1...Moreover, LJH685 sensitized MV4-11 significantly to BH3 mimetics, such as venetoclax or A-1210477, which inhibits Bcl-2 or Mcl-1, respectively. Our findings reveal that FLT3-ITD but not BCR/ABL activates RSK1 as well as RSK2 and upregulates RSK1 expression to promote proliferation and survival of leukemic cells through upregulation of the mTORC1 pathway and modification of eIF4B in collaboration with the PI3K/Akt and STAT5/PIM pathways and additionally through inhibitory modification of the proapoptotic proteins Bad and Bim (Figure). Thus, RSK1 represents a promising molecular target particularly in combination with PIM or PI3K for novel therapeutic strategies against therapy-resistant FLT3-ITD-positive AML.