This work shows that ERK inhibitors are effective in LKB1 and LKB1/KRAS mutated tumors, thus offering a therapeutic strategy for this prognostically unfavorable subgroup of patients.
Intriguingly, however, analogous oncogenic mutations in the downstream effector kinase ERK have not been described or validated <i>in vivo</i> To determine if a point mutation could render ERK intrinsically active and oncogenic, we have assayed in <i>Drosophila</i> the effects of a mutation that confers constitutive activity upon a yeast ERK ortholog, and which has been also identified in a few human tumors.
Moreover, the combination of an MEK or ERK inhibitor with a first-generation (eg, erlotinib) or second-generation (eg, afatinib) EGFR-TKI also very effectively inhibited the growth of osimertinib-resistant cells in vitro and of tumors in vivo, although these cell lines were cross-resistant to first-generation or second-generation EGFR-TKIs.
Once a broad tumor class is established, more specific differentiation markers can be pursued (e.g., lineage-restricted transcription factors for adenocarcinoma; p40 for squamous cell carcinoma; chromogranin A and synaptophysin or INSM1 for neuroendocrine neoplasms).
Hyperoside markedly inhibited diffuse epidermal hyperplasia and significantly reduced the changes in phosphorylated levels of PI3K, AKT, mTOR and AMPK while reducing p38 phosphorylation as well as of tumor burden <i>in vivo</i> in DMBA/TPA induced skin tumors.
Taken together, VPS33B as a tumor suppressor is easily dysregulated by chemical carcinogens and it interacts with NESG1 to modulate the EGFR/RAS/ERK/c-Myc/p53/miR-133a-3p feedback loop and thus suppress the malignant phenotype of CRC.
Meanwhile, treating GC cells with human recombinant FGF18 or FGF18-conditioned medium accelerated tumor growth through activation of ERK-MAPK signaling.
RNA-seq analysis revealed that ARQ531 constrained tumor cell proliferation and survival through Bruton's tyrosine kinase and transcriptional program dysregulation, with proteasome-mediated MYB degradation and depletion of short-lived proteins that are crucial for tumor growth and survival, including ERK, MYC and MCL1.
The 4-year progression-free survival rate, but not overall survival rate, was significantly higher in patients with KRAS-negative tumors than in those with KRAS-positive tumors (<i>P</i> < 0.05), whereas BRAF, MEK, and ERK expression was unrelated to survival.
The PAC010 model showed increased cell proliferation (Ki-67 staining) and markers indicating survival (increased p-AKT, p-ERK and p-NF-kB65 and suppression of cleaved PARP).
In the circumstance of miR-145 elevation or HOXA1 depletion, the SCC-9 cell line manifested with inhibited cell viability, invasion, and migration <i>in vitro</i>, coupled with reduced tumor growth <i>in vivo</i>, with a decreased expression of ERK/MAPK signaling pathway-related genes/proteins.
Hinokitiol rapidly induced ERK phosphorylation followed by a sustained dephosphorylation, which accompanied with an increase in expression of tumor suppressor MKP-3 (mitogen-activated protein kinase phosphatase-3).
Furthermore, patients with RAS/RAF/MEK/ERK pathway mutations (38.5%) showed significantly better tumour response (p = 0.028), PFS (5.4 vs. 3.5 months, p = 0.010) and OS (10.8 vs. 5.9 months, p = 0.160) than wild type.
Based on our previous findings that mutant <i>KRAS</i> knockdown sensitized NSCLC cells to a p38 inhibitor, the growth-inhibitory effect of dual MEK and p38 inhibition on tumor growth in NSCLC cells harboring <i>KRAS</i> mutations was investigated.
Tumor specific microenvironment including inflammatory factors is key mediator for maintaining the stemness of CSCs through various pathways such as p38 MAPK.