Molecular correlates of response to capmatinib in advanced non-small-cell lung cancer: clinical and biomarker results from a phase I trial

Schüler, Martin; Berardi, Rossana; Lim, Darren Wan-Teck; Jonge, Maja de; Bauer, Todd M.; Azaro, Analía; Gottfried, Maya; Han, Ji‐Youn; Lee, D. H.; Wollner, Mira; Hong, David S.; Vogel, Arndt; Delmonte, Angelo; Akimov, Mikhail; Ghebremariam, Samson; Cui, Xiaoming; Nwana, Ngozi; Giovannini, Monica; Kim, T. M.

doi:10.1016/j.annonc.2020.03.293

Cited by 75 publications

(81 citation statements)

References 31 publications

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“…Interestingly, very-high MET mRNA expression closely correlated with MET gene amplification by NGS or FISH and was mutually exclusive with METΔex14. Therefore, it is not surprising that the phenotype of the patients with very-high MET mRNA agrees with the characteristics previously reported in patients with high MET amplification (defined as FISH gene copy number, GCN≥6 or ≥10) [16,17,39,40].…”

Section: Accepted Articlesupporting

confidence: 86%

Multiplex RNA‐based detection of clinically relevant MET alterations in advanced non‐small cell lung cancer

et al. 2020

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MET inhibitors have shown activity in non-small cell lung cancer patients (NSCLC) with MET amplification and exon 14 skipping (METΔex14). However, patient stratification is imperfect and thus response rates have varied widely. Here, we studied MET alterations in 474 advanced NSCLC patients by nCounter, an RNA-based technique, together with Next Generation Sequencing (NGS), fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) and reverse transcriptase polymerase chain reaction (RT-PCR), exploring correlation with clinical benefit. Of the 474 samples analyzed, 422 (89%) yielded valid results by nCounter, which identified 13 patients (3%) with METΔex14 and 15 patients (3.5%) with very-high MET mRNA expression. These two subgroups were mutually exclusive, displayed distinct phenotypes and did not generally co-exist with other drivers. For METΔex14, 3/8 (37.5%) samples positive by nCounter tested negative by NGS. Regarding patients with very-high MET mRNA, 92% had MET amplification by FISH and/or NGS. However, FISH failed to identify three patients (30%) with very high MET RNA expression, among which one received MET tyrosine kinase inhibitor treatment deriving clinical benefit. Our results indicate that quantitative mRNA-based techniques can improve the selection of patients for MET-targeted therapies.

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Section: Accepted Articlesupporting

confidence: 86%

Multiplex RNA‐based detection of clinically relevant MET alterations in advanced non‐small cell lung cancer

et al. 2020

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“…Our mechanistic experiments showed that miR-34a directly interacts with the proto-oncogene MET and attenuates the MET signaling axis by posttranscriptional gene regulation in cancer cells. Activating point mutations of MET and MET ampli cation have been reported in several cancer types, including gastric cancer (65), breast cancer (66), hepatocellular carcinoma (67,68) and non-small cell lung cancer (69,70). MET plays an important role in the occurrence, development, invasion and metastasis of malignant tumors (69,(71)(72)(73).…”

Section: Discussionmentioning

confidence: 99%

“…Activating point mutations of MET and MET ampli cation have been reported in several cancer types, including gastric cancer (65), breast cancer (66), hepatocellular carcinoma (67,68) and non-small cell lung cancer (69,70). MET plays an important role in the occurrence, development, invasion and metastasis of malignant tumors (69,(71)(72)(73). While MET is a validated drug target in lung cancer, the best biomarker strategy for enrichment of a susceptible patient population still remained unde ned (69), and its role in HNSCC was not well known.…”

Section: Discussionmentioning

confidence: 99%

“…MET plays an important role in the occurrence, development, invasion and metastasis of malignant tumors (69,(71)(72)(73). While MET is a validated drug target in lung cancer, the best biomarker strategy for enrichment of a susceptible patient population still remained unde ned (69), and its role in HNSCC was not well known. We found high expression of MET throughout the entire epithelium in oral cancer in contrast to a partial staining in oral dysplastic lesions and no expression in normal tissue.…”

Section: Discussionmentioning

confidence: 99%

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Down-regulation of tumor suppressor miR-34a contributes to head and neck cancer by up-regulating MET oncogene and modulating tumor immune evasion

Cheng

Mathew

et al. 2020

Preprint

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Background: MicroRNAs (miRs) have been shown to play an important role in tumorigenesis, including in head and neck squamous cell carcinoma (HNSCC). The miR-34a family is thought to play a role in tumor suppression, but the exact mechanism of action in HNSCC is not well understood. In addition, miR-34a is generally down-regulated HNSCC, but the role of chromosomal changes and mutation status on miR-34a expression remain unknown. Methods: Differential expression of miR-34a-3p, MET, and genomic alterations were assessed in the Cancer Genome Atlas (TCGA) datasets as well as primary HNSCC and adjacent normal tissue. The biological functions of miR-34a in HNSCC were investigated in samples derived from primary human tumors. The expression of MET was evaluated using immunohistochemistry, and the molecular interaction of miR-34a and MET were demonstrated by RNA pulldown, RNA immunoprecipitation, and rescue experiments. Lastly, mouse xenograft and locked nucleic acid anti-miRs were used to evaluate the clinical relevance of miR-34a in HNSCC tumor growth and modulation of the tumor microenvironment in vivo.Results: Chromosome arm 1p loss and P53 mutations are both associated with lower levels of miR-34a. In HNSCC, miR-34a acts as a tumor suppressor and physically interacts with and functionally targets the proto-oncogene MET. We found that miR-34a suppresses HNSCC carcinogenesis, at least in part, by downregulating MET, consequently inhibiting HNSCC proliferation. Moreover, ectopic expression of miR-34a reduces HNSCC cell proliferation and tumor burden in vitro and in vivo, represses expression of genes involved in epithelial-mesenchymal transition, and negates the oncogenic effect of MET in mouse tumors. In HNSCC patient samples, higher levels of miR-34a are significantly associated with a higher frequency of Th1 cells, myeloid cells, and regulatory T cells. Consistent with these findings, inhibition of miR-34a in an in vivo model of HNSCC leads to an increased number of immunosuppressive PDL1-expressing tumor-associated macrophages in the tumor microenvironment. Conclusions: Our results demonstrate that miR-34a directly targets MET and maintains anti-tumor immune activity, and could potentially represent a new therapeutic approach for HNSCC.

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“…Other studies have reported favorable results with capmatinib in this setting [ 229 ]. With these data, capmatinib obtained the FDA approval in May 2020 for the treatment of patients with advanced NSCLC and a MET exon-14-skipping mutation.…”

Section: Tyrosine Kinase Receptor Inhibitors Developed For Cancer mentioning

confidence: 92%

Tyrosine Kinase Receptors in Oncology

Esteban-Villarrubia

Castillo

Pozas

et al. 2020

IJMS

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Tyrosine kinase receptors (TKR) comprise more than 60 molecules that play an essential role in the molecular pathways, leading to cell survival and differentiation. Consequently, genetic alterations of TKRs may lead to tumorigenesis and, therefore, cancer development. The discovery and improvement of tyrosine kinase inhibitors (TKI) against TKRs have entailed an important step in the knowledge-expansion of tumor physiopathology as well as an improvement in the cancer treatment based on molecular alterations over many tumor types. The purpose of this review is to provide a comprehensive review of the different families of TKRs and their role in the expansion of tumor cells and how TKIs can stop these pathways to tumorigenesis, in combination or not with other therapies. The increasing growth of this landscape is driving us to strengthen the development of precision oncology with clinical trials based on molecular-based therapy over a histology-based one, with promising preliminary results.

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Molecular correlates of response to capmatinib in advanced non-small-cell lung cancer: clinical and biomarker results from a phase I trial

Cited by 75 publications

References 31 publications

Multiplex RNA‐based detection of clinically relevant MET alterations in advanced non‐small cell lung cancer

Multiplex RNA‐based detection of clinically relevant MET alterations in advanced non‐small cell lung cancer

Down-regulation of tumor suppressor miR-34a contributes to head and neck cancer by up-regulating MET oncogene and modulating tumor immune evasion

Tyrosine Kinase Receptors in Oncology

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