Tracing the origin: How does the MET exon 14 skipping mutation cause cancer?

*For medical professionals only for reference Explore MET exon 14 skipping mutation in NSCLC! In recent years, targeted therapy has achieved great success in the treatment of non-small cell lung cancer (NSCLC) patien.
Targeted therapy has gradually replaced traditional chemotherapy as the standard treatment for patients with advanced NSC.
Mesenchymal-epithelial transforming factor (MET) is considered to be another important molecular therapeutic target for NSCLC after epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (AL.
There are many types of abnormal activation of MET pathway, including MET exon 14 skipping mutation, MET amplification, MET rearrangement and MET protein overexpression[1-
Among these MET pathway abnormalities, targeted drugs targeting MET exon 14 skipping mutations have been approved for indications in Chi.
 In 2014, the American Cancer Genome Research Group (TCGA) conducted sequence alignment analysis on the mRNA and DNA high-throughput sequencing results of 230 lung adenocarcinoma patients and found that about 4% of lung adenocarcinoma patients had MET exon 14 skipping mutatio.
Since then, it has attracted people's attention as a newly discovered MET anomaly [
How do MET exon 14 skipping mutations cause cancer? What are the characteristics of the patient? How should it be treated? Let's go back to the roots togeth.
By what mechanism do MET exon 14 skipping mutations cause cancer? Under normal circumstances, when MET binds to the ligand HGF, it dimerizes and causes the phosphorylation of various tyrosine residues in the cell, which in turn activates a series of downstream signaling pathways, including Ras-MAPK, PI3KAkt, e.
It promotes cell proliferation, growth, migration and angiogenes.
MET is degraded by the E3 ubiquitin ligase c-C.
The juxtamembrane domain encoded by MET exon 14 is a key negative regulatory region of MET, containing a caspase cleavage sequence and an E3 ubiquitin ligase c-Cbl tyrosine binding site (Y1003), which is involved in MET Ubiquitination and degradation of proteins [3] (F.
1.
 Under normal circumstances, the introns flanking MET exon 14 are spliced ​​out in the pre-mRNA, allowing the mRNA containing MET exon 14 to be translated into a functional MET recept.
 Mutations in the splicing donor and acceptor sites of exon 14 of MET cause exon skipping and deletion of the juxtamembrane domain containing the E3 ubiquitin ligase c-Cbl,.

, a truncation of the deletion of Y1003 and c-Cbl binding sit.

The short-type MET receptor, in turn, reduces the ubiquitination barrier and degradation rate of MET protein, increases the stability of MET, and causes continuous activation of downstream signals, eventually becoming an oncogenic factor [3] (Figure 1.

FigureMolecular mechanism of MET exon 14 skipping mutatio.

In fact, there are more than 160 different mutations affecting MET exon 14, including base pair point mutations, deletions, insertions, or complex mutations (indels), all of which Sequences of donor or acceptor sites affecting intron splice junctions around exon 14 [
What are the characteristics of patients with MET exon 14 skipping mutations? Molecular analysis of 38,028 tumor samples by next-generation sequencing (NGS) technology found that MET exon 14 can occur in various advanced cancers, but the incidence is low, including lung cancer, gastric cancer, colorectal cancer, e.

[4].

 The MET exon 14 skipping mutation is considered an independent oncogenic driver gene and does not coexist with other driver mutatio.

The study found that genetic testing of 933 NSCLC patients found that 28 NSCLC patients had MET exon 14 skipping mutations, accounting for about 0%, and none of these 28 patients had EGFR or KRAS mutations [
However, cyclin-dependent kinase 4 (CDK4) amplification and EGFR amplification have been found to coexist with MET exon 14 skipping mutations [
 MET exon 14 skipping mutations may occur in different major histological subtypes of lung cancer, such as adenosquamous carcinoma, pulmonary sarcomatoid carcinoma (PSC), adenocarcinoma, and squamous cell carcino.

PSC is a unique subtype in the NSCLC patient population, and PSC patients have a higher rate of MET exon 14 skipping mutatio.

It has been reported that the incidence of MET exon 14 skipping mutation in PSC patients can be as high as 38% [
 The effect of MET exon 14 skipping mutations on survival has not been extensively studi.

A related study conducted a survival analysis of 687 untreated NSCLC patients at different stag.

Multivariate analysis showed that MET exon 14 skipping mutation was an independent poor prognostic factor for advanced NSCLC[
 In addition, the MET exon 14 skipping mutation population was older and had a history of smoki.

Relevant reports showed that the median age of patients with MET exon 14 skipping mutations was 75 years, 68% were female and 64% were smoke.

Compared with patients with EGFR mutation (median age 61 years) and KRAS mutation patients (median age 65 years), patients with MET exon 14 skipping mutation were older (P<001) [
MET-TKI brings more benefits to patients with MET exon 14 skipping mutati.

Patients with MET exon 14 skipping mutation have a higher risk of death, and the efficacy of chemotherapy and immunotherapy is not satisfacto.

Data from studies on MET exon 14 skipping NSCLC showed that the objective response rate (ORR) of PD-1 inhibitors and PD-L1 inhibitors in MET exon 14 skipping NSCLC was 1
Although NSCLC patients with MET exon 14 skipping mutations have PD-L1 expression, this population is less effective for immunothera.

Looking forward to follow-up related clinical trials to further explore the specific mechanism of immunotherapy insensitivity in this population, and the real efficacy of immunotherapy in MET exon 14 skipping mutation NSCLC still needs to be further explored [
 In recent years, more and more evidence has shown that MET inhibitors have achieved good anti-tumor effects in patients with MET exon 14 skipping mutations, suggesting that MET exon 14 skipping mutations may be a new target for the treatment of NSCLC patien.

At present, the targeted drugs acting on the MET exon 14 skipping mutation mainly include monoclonal antibodies and small molecule tyrosine kinase inhibitors (TKI.

TKIs targeting MET are selective competitive inhibitors of adenosine triphosphate (ATP), which inhibit the phosphorylation of downstream related kinases by inhibiting the activity of MET, thereby arresting downstream signal transduction, thereby regulating tumor cell proliferation, metastasis and blood vesse.

fo.

 With the continuous development of new drugs, MET-TKI has achieved good antitumor effect in NSCLC patients with MET exon 14 skipping mutati.

A Phase II clinical study [7] led by Professor Lu Shun of the Chest Hospital Affiliated to Shanghai Jiaotong University showed that the disease control rate (DCR) of sevolitinib treatment reached 94%, and the objective response rate (ORR) was 4
At the 2022 European Lung Cancer Congress (ELCC) [8], the study presented the final overall survival (OS) results for the first ti.

Sevolitinib resulted in a median OS of 15 months and a median progression-free survival (PFS) of 9 months in the overall population with MET exon 14 skipping mutations, with a favorable long-term safety profi.

In addition, in the phase II VISION study, tepotinib has durable clinical activity in patients with MET exon 14 skipping mutation NSCLC, the overall population ORR is 47%, and the safety is good [
The GLORY study showed that the ORR of the total population of gumetinib was 69%, and the ORR of the newly treated patients was slightly better than that of the previously treated patients, 67% and 59%, respectively, showing a good clinical benefit [1
 With the in-depth research on MET targets, NSCLC patients with MET exon 14 skipping mutation will obtain better curative effect and long-term surviv.

Drug resistance is one of the challenges of targeted therapy at this sta.

In the future, researchers will conduct in-depth research on the drug resistance mechanism of MET exon 14 skipping mutation and MET-TKI combination thera.

Looking forward to the prospect of drugs targeting MET targets in the country in the future, bringing more good news to tumor patients! References: [1] Olivier Bylicki, Nicolas Paleiron, et, .

Targeting the MET-Signaling Pathway in Non-Small–Cell Lung Cancer: Evidence to DateOnco Targets Th.

2020; 13: 5691–5706 [2] Huang C, et .

Management of Non-small Cell Lung Cancer Patients with MET Exon 14 Skipping Mutatio.

Curr Treat Options Onc.

2020;21(4): 3[3] Yin Limei, Lu .

MET Exon 14 Skipping Mutations in Non-small Cell Lung Cancer Patien.

Research progress in small cell lung cancer[.

China Lung Cancer Journ.

2018;7(21)553-55[4]Cortot AB, et .

Exon 14 Deleted MET Receptor as a New Biomarker and Target in Cance.

J Natl Cancer In.

2017;109(
[5]Tong JH, Yeung SF, Chan AWH, et .

MET amplification and exon 14 splice site mutation define unique molecular subgroups of non–small cell lung carcinoma with poor prognosis[J.

Clinical Cancer Research, 2016, 22(12): 3048-305[6] Yang Guangjian, Wang Yan, Research progress in the treatment of rare gene mutations in non-small cell lung cancer[.

Cancer Progress, 2019 ;17 (12)[7 ]Lu S, Fang J, Li, .

Relevant parties are requested to check separately when adopting or using it as a basis for decision-maki.