METex14 is a type of MET dysregulation that plays a role in oncogenesis1
Patients with METex14 in NSCLC face a poor prognosis2,3
- METex14 in mNSCLC has a prevalence of ~3%, representing ~4,000-5,000 patients in the United States* and ~53,300 patients worldwide per year4-7
- METex14 was found to be an independent prognostic factor that predicted worse survival outcomes in patients with NSCLC than in patients with NSCLC without MET alteration2,3
Bone, brain, and liver metastases in patients with NSCLC
Based on a retrospective analysis (N=148)9,10,b
aData from a retrospective study evaluating 543 patients with stage IV NSCLC, including 121 patients who tested positive for EGFR mutations. Patients were evaluated for the impact of EGFR mutations on the pattern of metastasis.
bData from a retrospective study evaluating 148 patients with stage IV METex14 NSCLC. Sites of metastasis were studied as part of the clinicopathologic characteristics of the patient.
*This calculation is based on a 3% prevalence rate and mNSCLC-specific incidence and recurrence data from Kantar Health.
MET normally plays an important role in cell signaling, proliferation, and survival1,11
- MET (mesenchymal-epithelial transition) factor is a receptor tyrosine kinase coded by the MET gene, and is expressed on the surfaces of various epithelial cells12
- When HGF binds to the MET receptor, it activates downstream pathways and triggers cell growth, proliferation, and survival13
Dysregulation of MET and HGF signaling leads to malignant cellular transformation, proliferation, survival, angiogenesis, invasion, and metastasis12
MET dysregulation can occur through a variety of mechanisms
Occurs when there are too many copies of the MET receptor14
The role of MET receptor overexpression is unclear1
An increase in the number of copies of the MET gene15
MET amplification can occur as an oncogenic event or a mechanism of resistance1
Most commonly caused by splice site alterations1
METex14 is an oncogenic alteration in NSCLC1
A chromosomal rearrangement leading to gene fusion, resulting in a chimeric MET protein16
MET rearrangements/fusions are rare mechanisms, and their role as oncogenic alterations is unclear1
METex14 is an oncogenic alteration1
- METex14 can result in overstimulation of the MET pathway17
- METex14 leads to deletion of the juxtamembrane domain, which is involved in MET protein degradation, resulting in the persistence and overabundance of MET receptors18
- METex14 can occur early and is present throughout NSCLC development1,9
- Many patients are not diagnosed with NSCLC until their disease has progressed to later stages9
AKT, protein kinase B; BRAF, v-raf murine sarcoma viral oncogene homolog B1; EGFR, epidermal growth factor receptor; HGF, hepatocyte growth factor; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; METex14, MET exon 14 skipping; mNSCLC, metastatic non-small cell lung cancer; mTOR, mechanistic target of rapamycin; PI3K, phosphoinositide 3-kinase; STAT 3/5, signal transducer and activator of transcription 3/5.
BRAF V600E is a mutation in the BRAF gene that can drive oncogenesis19
BRAF V600E is associated with a poor prognosis20
- Approximately 2% of patients may have BRAF V600E, representing ~2,000-3,000 patients in the United States* and ~35,600 patients worldwide5-7,20,21
- BRAF V600E–mutated NSCLC is frequently associated with a more aggressive histotype characterized by micropapillary features20
A serine/threonine protein kinase, encoded by the BRAF gene, regulates normal cell growth22
- In preclinical models with BRAF-mutant NSCLC, the RAS-RAF-MEK-ERK pathway is rendered constitutively active by a V600E mutation in the BRAF oncogene, leading to uncontrolled signaling and tumor growth19,23
- The BRAF oncogene is associated with glutamate-to-valine amino acid substitution at codon 600 (V600; ie, Val600Glu) within exon 15 of the kinase domain. This leads to a 500-fold increase in the kinase activity of BRAF compared with BRAF wild type, according to preclinical models19
- The majority (>50%) of mutations in the BRAF oncogene are BRAF V600E in NSCLC20,25
ERK, extracellular signal-regulated kinase; RAF, rapidly accelerated fibrosarcoma; RAS, rat sarcoma; RTK, receptor tyrosine kinase.
*This calculation is based on a 2% prevalence rate and mNSCLC-specific incidence and recurrence data from Kantar Health.
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