Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019621 (Langerhans cell histiocytosis)
 3,250 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

P21-activated kinase 4 (PAK4), a serine/threonine protein kinase, has involved in the regulation of cytoskeletal reorganization, cell proliferation, gene transcription, oncogenic transformation and cell invasion. Moreover, PAK4 overexpression, genetic amplification and mutations were detected in a variety of human tumors, which make it potential therapeutic target. In this paper we found that LCH-7749944, a novel and potent PAK4 inhibitor, effectively suppressed the proliferation of human gastric cancer cells through downregulation of PAK4/c-Src/EGFR/cyclin D1 pathway. In addition, LCH-7749944 significantly inhibited the migration and invasion of human gastric cancer cells in conjunction with concomitant blockage of PAK4/LIMK1/cofilin and PAK4/MEK-1/ERK1/2/MMP2 pathways. Interestingly, LCH-7749944 also inhibited the formation of filopodia and induced cell elongation in SGC7901 cells. Importantly, LCH-7749944 caused successful inhibition of EGFR activity due to its inhibitory effect on PAK4. Taken together, these results provided novel insights into the development of PAK4 inhibitor and potential therapeutic strategies for gastric cancer.
 ...
PMID:LCH-7749944, a novel and potent p21-activated kinase 4 inhibitor, suppresses proliferation and invasion in human gastric cancer cells. 2208 92

Newly-appearing lung nodules on surveillance imaging in patients with pre-existing lung cancer can present a diagnostic dilemma when attempting to differentiate between metastatic disease, infection, and other inflammatory conditions. Here we report a case of an EGFR-/ALK-/BRAF+ metastatic adenocarcinoma patient who underwent lung biopsy for evaluation of upper-lobe predominant lung nodules revealed to represent pulmonary Langerhans cell histiocytosis (PLCH). The patient was a heavy smoker and admitted to increase her smoking habit after initially learning about her diagnosis with lung cancer. Interestingly, despite the association of both lung adenocarcinoma and PLCH with the BRAFV600E mutation in smokers, pyrosequencing of the patient's PLCH lesions was negative for this mutation. Co-occurrence of PLCH with lung cancer is extremely rare. While most reported cases of PLCH tend to precede the occurrence of lung cancer, a minority of cases appear after a diagnosis of lung cancer has already been established and are thought to represent a local immunologic reaction to the tumor. It is therefore postulated that the appearance of PLCH lesions in this patient's lungs is a result of her increase in cigarette smoking, possibly augmented by co-existence of adenocarcinoma.
 ...
PMID:Development of pulmonary Langerhans cell histiocytosis in a patient with established adenocarcinoma of the lung. 2931 70

Class 3 MEK1 mutations disrupt the negative regulatory helix region of MEK1 and drive constitutive activation of both pMEK and pERK that is independent of RAF and of MEK phosphorylation. Targeting MEK with trametinib resulted in mixed clinical responses in class 3 MEK1 mutated Langerhans cell histiocytosis (LCH). The ERK inhibitor, ulixertinib, demonstrated limited anti-tumor activity in non-characterized MEK1 mutated solid tumors, with 2 out 4 patients experiencing stable disease (SD). Here, we present the case of a 52-year-old female with metastatic colon cancer harboring a MEK1E102_I103del (class 3 mutation) who progressed on standard chemotherapy and showed no response to the MEK inhibitor trametinib, the ERK inhibitor ulixertinib, and the combination of ulixertinib and the anti-EGFR antibody panitumumab. Despite progressive disease (PD), the patient exhibited a steep but short-lived tumor marker response to MEK and ERK inhibition, suggesting the emergence of early mechanisms of resistance to MAPK pathway inhibition. This report presents the first case in the literature investigating a MEK inhibitor and an ERK inhibitor (alone and in combination with anti-EGFR therapy) in metastatic colorectal cancer harboring a class 3 MEK1 mutation (E102-I103 deletion).
 ...
PMID:A case of class 3 MEK1 mutated metastatic colorectal cancer with a non-durable tumor marker response to MEK and ERK inhibitors. 3194 31