Sequencing Studies Show High Frequency of Actionable MET Mutations in Pulmonary Sarcomatoid Carcinoma
In a study reported in the Journal of Clinical Oncology by Liu et al, next-generation sequencing revealed a high frequency of actionable MET mutations in patients with pulmonary sarcomatoid carcinoma.
Study Details
In the study, whole-exome sequencing was used in a discovery set of 10 patients and targeted MET mutation screening was performed in a validation set of 26 patients. Reverse transcriptase polymerase chain reaction and Western blotting were used to validate MET exon 14 skipping, and functional studies of the oncogenic roles of MET exon 14 skipping were performed in lung adenosquamous cell line H596 (MET exon 14 skipped and PIK3CA mutated) and gastric adenocarcinoma cell line Hs746T (MET exon 14 skipped).
MET Mutations
Sequencing confirmed mutations in known cancer-associated genes (TP53, KRAS, PIK3CA, MET, NOTCH, STK11, and RB1) and identified novel mutations in additional genes, including RASA1, CDH4, CDH7, LAMB4, SCAF1, and LMTK2. MET mutations leading to exon 14 skipping were identified in 8 (22%) of 36 patients, with one of the tumors exhibiting concurrent PIK3CA mutation.
Short interfering RNA silencing of MET and MET inhibition with crizotinib (Xalkori) showed a marked reduction in cell proliferation and reduction of downstream AKT and MAPK activation in the Hs746T and H596 cells. The presence of a concurrent PIK3CA mutation required the addition of a second agent for pathway suppression and reduced cell viability. A remarkable response to crizotinib treatment was observed in a patient with advanced chemotherapy-refractory disease harboring a MET exon 14 skipping mutation.
The investigators concluded: “Mutational events of MET leading to exon 14 skipping are frequent and potentially targetable events in [pulmonary sarcomatoid carcinoma].”
Balazs Halmos, MD, of Columbia University Medical Center, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by Uniting Against Lung Cancer and LUNGevity For full disclosures of the study authors, visit jco.ascopubs.org.
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