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MET Exon 14 Skipping: Biomarker & Targeted Therapy

MET Exon 14 Skipping is a genetic alteration primarily found in non-small cell lung cancer and serves as a key biomarker for targeted therapy decisions.

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Things worth knowing about "MET Exon 14 Skipping"

MET Exon 14 Skipping is a genetic alteration primarily found in non-small cell lung cancer and serves as a key biomarker for targeted therapy decisions.

What is MET Exon 14 Skipping?

MET Exon 14 Skipping (also referred to as METex14 skipping) is a specific genomic alteration in the MET gene in which the 14th exon is omitted during messenger RNA (mRNA) processing. The MET gene encodes the hepatocyte growth factor receptor (c-MET), a receptor tyrosine kinase that plays critical roles in cell growth, division, and migration. The loss of exon 14 removes an important regulatory domain of the receptor, resulting in persistent activation of the MET signaling pathway and uncontrolled cell proliferation.

Causes and Molecular Background

The alteration arises from mutations in the splice site regions surrounding exon 14 of the MET gene – the sequences that control precise cutting and joining of RNA segments. As a result, exon 14 is skipped during RNA splicing. This leads to the loss of the juxtamembrane domain of the MET receptor, which contains the binding site for the E3 ubiquitin ligase adapter protein CBL. Without this binding site, the receptor can no longer be properly degraded and remains persistently active.

Point mutations in the splice donor or splice acceptor sites of intron 13 or intron 14
Deletions within exon 14 or its flanking intronic regions
Less commonly: chromosomal rearrangements

Clinical Significance and Prevalence

MET Exon 14 Skipping occurs in approximately 3–4% of all non-small cell lung cancers (NSCLC), making it one of the most common MET alterations in this malignancy. The alteration is more frequently observed in older patients and in pulmonary sarcomatoid carcinoma, a rare and aggressive subtype of NSCLC. Less commonly, METex14 skipping has also been reported in other tumor types, including gastric cancer and brain tumors.

Diagnosis

Detection of MET Exon 14 Skipping is performed through molecular pathology testing of tumor tissue or a liquid biopsy (blood sample). The following methods are used:

Next-Generation Sequencing (NGS): Comprehensive DNA- and RNA-based sequencing; considered the gold standard as it captures alterations at both the DNA and RNA level
RT-PCR (Reverse Transcriptase Polymerase Chain Reaction): Detection at the RNA level
Liquid Biopsy: Analysis of circulating tumor DNA (ctDNA) from blood as a less invasive alternative

Because the alteration must be detected at both the DNA and RNA level, international guidelines recommend RNA-based NGS or combined DNA/RNA panels for reliable identification.

Treatment: Targeted Therapy

MET Exon 14 Skipping is a recognized predictive biomarker that supports the use of MET inhibitors. These agents specifically block the overactivated MET kinase, thereby inhibiting tumor growth.

Approved MET Inhibitors

Capmatinib (Tabrecta®): The first specific MET inhibitor approved for NSCLC with METex14 skipping (FDA 2020, EMA 2022)
Tepotinib (Tepmetko®): Another approved selective MET inhibitor for NSCLC with METex14 skipping (EMA 2022, FDA 2022)

Additional Therapeutic Options

Crizotinib: A first-generation MET/ALK/ROS1 inhibitor that also shows activity in METex14 skipping, though less specific
Combination therapies and novel MET inhibitors (e.g., savolitinib) are being further investigated in clinical trials

Importantly, resistance mechanisms to MET inhibitors – particularly secondary MET mutations or activation of alternative signaling pathways (e.g., EGFR, KRAS) – are the subject of ongoing research.

Prognosis

The prognosis for patients with METex14-skipping-positive NSCLC has historically been less favorable than for other oncogenic driver mutations. With the introduction of targeted MET inhibitors, response rates of up to 40–68% and improved progression-free survival times have been achieved. Nevertheless, prognosis remains challenging, particularly in older patients and those with significant comorbidities.

References

Wolf J et al. - Capmatinib in MET Exon 14-Mutated or MET-Amplified Non-Small-Cell Lung Cancer. New England Journal of Medicine, 2020.
Paik PK et al. - Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations. New England Journal of Medicine, 2020.
European Medicines Agency (EMA) - Tepmetko (Tepotinib) and Tabrecta (Capmatinib): Product Information and Assessment Reports. EMA, 2022.

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