Evidence continues to grow for the potential therapeutic benefit of mesenchymal-epithelial transition factor proto-oncogene (MET) inhibition to treat non-small cell lung cancer (NSCLC). A recent study by Tong et al. (1) published this past June on MET DNA alterations in NSCLC provides further evidence of the critical role of aberrant MET signaling in the pathogenesis of NSCLC, including the sarcomatoid carcinoma subtype. This subtype of NSCLC is highly aggressive and chemo-resistant, and is often difficult to diagnose (2). The study was aimed at determining the prevalence of MET DNA alterations in a large cohort of Chinese lung cancer patients, and defined the clinicopathological characteristics of MET-positive tumors. The study found oncogenic MET DNA alterations in 3.3% of NSCLC patients with aggressive diseases and older age, and supported the possibility of using MET inhibition to potentially treat this type of NSCLC. Conclusions from this new study on the Chinese population confirm earlier findings (3, 4) and provide further evidence that NSCLC patients may benefit from MET targeted therapies.
The significance of MET exon 14 deletion mutations in NSCLC tumorigenesis was reported in a large sample cohort in August 2015 by Frampton et al. (3), who described a diverse array of mutations that caused a defect in MET exon 14 splicing and were found to confer constitutive activity and oncogenic transformation to this receptor in vitro. This study provided initial evidence of the role of MET exon 14 alterations as tumorigenic drivers, and identified a unique subset of patients likely to benefit from MET inhibitors. MET exon 14 alterations are highly diverse in sequence composition, many are novel and more than half are large indel mutations. These characteristics make it difficult to detect MET exon 14 alterations with high sensitivity and specificity, posing a challenge for diagnostic testing and assessment of MET exon14 alterations (1).
Later, a study by Awad et al. (4) published recently in the Journal of Clinical Oncology confirmed that MET exon 14 mutations represent a specific clinical and molecular subtype of NSCLC. These MET mutations were again found in 3% of the nonsquamous NSCLC patients tested, and clinical characteristics among these patients were compared with those of NSCLC patients with activating mutations in KRAS and EGFR. They found that patients with MET exon 14 mutations tended to be several years older than patients with EGFR or KRAS mutations, findings which align with those later found by Tong et al. The study by Awad et al calls for prospective clinical trials with c-MET inhibitors to validate MET as an important therapeutic target in NSCLC.
That is exactly what Mirati_Therapeutics is working on at the moment (5). Mirati, whose name very appropriately means “targeted” in Italian, is now conducting clinical assessment of the effects of drug candidate MGCD265 (glesatinib), a tyrosine kinase inhibitor (TKI) that potently and selectively targets tumors in patients with driver alterations in MET and AXL. If approved, around 8% of patients with NSCLC could potentially benefit from this targeted therapy. Glesatinib is currently under phase 2 clinical trial evaluation in NSCLC patients (as well as patients with other tumor types) with MET genetic alterations. This clinical study aims to both confirm and expand upon existing data supporting the clinical benefit of glesatinib in patients with driver mutations in MET.
Earlier this year, we announced in a press release that QIAGEN entered into a partnership with Mirati Therapeutics to co-develop and commercialize a companion diagnostic test to guide the use of glesatinib (6). This exciting collaboration has great potential to extend targeted diagnostic capabilities and personalized healthcare in NSCLC, and future projects may expand across various sample types and platforms, such as PCR and NGS.
QIAGEN continues to expand its portfolio of Sample to Insight technologies for oncology through collaborations such as the partnership with Mirati. Find out more about QIAGEN’s oncology companion diagnostics solutions in the US and oncology solutions available throughout Europe.
- 1. Tong et al. (2016) MET Amplification and Exon 14 Splice Site Mutation Define Unique Molecular Subgroups of Non-Small Cell Lung Carcinoma with Poor Prognosis. Clin Cancer Res. 22(12):3048-56. doi: 10.1158/1078-0432.CCR-15-2061. (Link)
- 2. Franks, T.J. and Galvin, J.R. (2010) Sarcomatoid Carcinoma of the Lung: Histologic Criteria and Common Lesions in the Differential Diagnosis. Arch Pathol Lab Med. 134:49–54. (Link)
- 3. Frampton, G.M. et al (2015) Activation of MET via Diverse Exon 14 Splicing Alterations Occurs in Multiple Tumor Types and Confers Clinical Sensitivity to MET Inhibitors. Cancer Discov. 5(8):850-9. doi: 10.1158/2159-8290. (Link)
- 4. Awad et al. (2016) MET Exon 14 Mutations in Non-Small-Cell Lung Cancer Are Associated With Advanced Age and Stage-Dependent MET Genomic Amplification and c-Met Overexpression. J Clin Oncol. 34(7):721-30. doi: 10.1200/JCO.2015.63.4600. (Link)
- 5. NCT00697632: Safety Study of Oral MGCD265 Administered Without Interruption to Subjects With Advanced Malignancies. (Link)
- 6. Press Release April 13, 2016: QIAGEN partners to develop novel companion diagnostic in lung cancer. (Link)