Targeted Therapy Approaches for MET Abnormalities in Non-Small Cell Lung Cancer

Garon, Edward B.; Brodrick, Paige

doi:10.1007/s40265-021-01477-2

Cited by 20 publications

(33 citation statements)

References 64 publications

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“…Obviously, the physiological activities commenced by Met-signaling in DC and other immune cells suggest, on the one hand, that the HGF/Met pathway could be a potential target for the treatment of inflammatory diseases, autoimmune disorders, and transplantation (Molnarfi et al, 2015;Ilangumaran et al, 2016). On the other hand, aberrant Met-signaling and overexpression of HGF have been associated with tumor progression and metastasis, thus the Met RTK is emerging as a promising therapeutic target for cancer treatment (Trusolino et al, 2010;Gherardi et al, 2012, Garon andBrodrick, 2021). Remarkably, it was reported that specific Met ablation in neutrophils, impaired their recruitment to the tumor tissue, thus enhancing tumor growth and metastasis (Finisguerra et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Met-signaling Controls Dendritic Cell Migration by Regulating Podosome Formation and Function

Hamouda

Schalla

Sechi

et al. 2021

Preprint

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Signaling by the HGF receptor/Met in skin-resident Langerhans cells (LC) and dermal dendritic cells (dDC) is essential for their emigration toward draining lymph nodes upon inflammation-induced activation. By employing a conditional Met-deficient mouse model (Metflox/flox) we addressed the role of Met-signaling in distinct steps of LC/dDC emigration from skin. Met deficiency did not prevent the decline in expression of the adhesion molecules E-cadherin and EpCAM in LC upon activation and consequently detachment from the surrounding tissue and migration towards dermis. However, Met-deficient LC failed to efficiently cross the extracellular matrix (ECM) rich basement membrane between epidermis and dermis. We found that Met deficiency severely impaired podosome formation in DC and concomitantly decreased proteolytic degradation of gelatin. We further observed that Met-signaling by HGF reduced adhesion of bone marrow-derived LC to various ECM factors and enhanced the motility of Met-signaling competent DC in a 3D collagen matrix, which was not the case for Met-deficient LC/DC. In contrast, we found no impact of Met-signaling on the integrin-independent amoeboid migration of DC in response to the CCR7 chemokine CCL19. Collectively, our data show that the Met-signaling pathway regulates the migratory properties of DC in HGF-dependent and HGF-independent manners.

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Section: Discussionmentioning

confidence: 99%

Met-signaling Controls Dendritic Cell Migration by Regulating Podosome Formation and Function

Hamouda

Schalla

Sechi

et al. 2021

Preprint

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“…The best example until now has been non-small-cell lung cancer (NSCLC), in which MET exon 14 skipping mutations affecting the corresponding splicing sites and MET-GCNG/GA occur in 3–5% and 1–6% of cases, respectively [ 2 , 3 , 4 , 5 ]. Overexpression of MET protein has been reported in 25 to 75% of cases, depending on the antibody and cutoff value used in the implemented immunohistochemistry (IHC) assays as well as the histological NSCLC subtypes analyzed [ 2 , 3 , 4 , 5 ]. MET overexpression, MET-GCNG/GA, and MET exon 14 skipping mutations are considered negative prognostic markers in NSCLC [ 3 , 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…Overexpression of MET protein has been reported in 25 to 75% of cases, depending on the antibody and cutoff value used in the implemented immunohistochemistry (IHC) assays as well as the histological NSCLC subtypes analyzed [ 2 , 3 , 4 , 5 ]. MET overexpression, MET-GCNG/GA, and MET exon 14 skipping mutations are considered negative prognostic markers in NSCLC [ 3 , 4 , 5 ]. Inhibition of MET signaling is currently achievable in NSCLC patients using the MET/ALK/ROS tyrosine-kinase inhibitor (TKI) Crizotinib or selective MET-TKIs (Capmatinib, Savolitinib, Tepotinib, Cabozantinib), or MET or HGF monoclonal antibodies (mAbs), as well as MET or HGF antibody–drug conjugates [ 2 , 3 , 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…MET overexpression, MET-GCNG/GA, and MET exon 14 skipping mutations are considered negative prognostic markers in NSCLC [ 3 , 4 , 5 ]. Inhibition of MET signaling is currently achievable in NSCLC patients using the MET/ALK/ROS tyrosine-kinase inhibitor (TKI) Crizotinib or selective MET-TKIs (Capmatinib, Savolitinib, Tepotinib, Cabozantinib), or MET or HGF monoclonal antibodies (mAbs), as well as MET or HGF antibody–drug conjugates [ 2 , 3 , 4 , 5 ]. In addition to MET exon 14 skipping mutations identified by next-generation sequencing (NGS) of DNA or RNA, MET-expression analyzed by IHC and MET-GCNG/GA status evaluated by fluorescence in situ hybridization (FISH) are considered biomarkers for targeted anti-MET therapy in NSCLC [ 3 , 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…Inhibition of MET signaling is currently achievable in NSCLC patients using the MET/ALK/ROS tyrosine-kinase inhibitor (TKI) Crizotinib or selective MET-TKIs (Capmatinib, Savolitinib, Tepotinib, Cabozantinib), or MET or HGF monoclonal antibodies (mAbs), as well as MET or HGF antibody–drug conjugates [ 2 , 3 , 4 , 5 ]. In addition to MET exon 14 skipping mutations identified by next-generation sequencing (NGS) of DNA or RNA, MET-expression analyzed by IHC and MET-GCNG/GA status evaluated by fluorescence in situ hybridization (FISH) are considered biomarkers for targeted anti-MET therapy in NSCLC [ 3 , 4 , 5 ]. Given intratumor heterogeneity, direct morphological assessment of MET-overexpression and MET-GCNG/GA in tumor specimens using IHC and FISH is deemed to be more sensitive than NGS-based assessment of MET-amplification and more informative as to whether the deregulated MET-receptor signaling can be targeted in a specific patient [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

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Correlation of MET-Receptor Overexpression with MET Gene Amplification and Patient Outcome in Malignant Mesothelioma

Santoni-Rugiu

Lü

Jakobsen

et al. 2021

IJMS

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Thanks to clinically newly introduced inhibitors of the mesenchymal–epithelial transition (MET) receptor tyrosine-kinase, MET-gene copy number gain/amplification (MET-GCNG/GA) and increased expression of the MET protein are considered very promising therapeutic targets in lung cancer and other malignancies. However, to which extent these MET alterations occur in malignant mesothelioma (MM) remains unclear. Thus, we investigated by well-established immunohistochemistry and fluorescence in situ hybridization methods, the frequency of these alterations in specimens from 155 consecutive MMs of different subtypes obtained from pleural or peritoneal biopsies and pleurectomies. Thirty-three benign reactive mesothelial proliferations (RMPs) were used as controls. MET-protein upregulation was observed in 35% of all MM-cases, though restricted to predominantly epithelioid MMs. We detected low-/intermediate-level MET-GCNG/GA in 22.2% of MET-overexpressing MMs (7.8% of whole MM-cohort) and no MET-GCNG/GA in the other 77.8%, suggesting other upregulating mechanisms. In contrast, 100% of RMPs exhibited no MET-upregulation or MET-GCNG/-GA. Neither MET exon 14 skipping mutations nor MET-fusions were detected as mechanisms of MET overexpression in MM using RNA next-generation sequencing. Finally, in two cohorts of 30 MM patients with or without MET overexpression (MET-positive/-negative) that were matched for several variables and received the same standard chemotherapy, the MET-positive cases showed a significantly lower response rate, but no significant difference in progression-free or overall survival. Our results imply that MET overexpression occurs in a substantial fraction of predominantly epithelioid MMs, but correlates poorly with MET-amplification status, and may impact the likelihood of response to mesothelioma standard chemotherapy. The predictive significance of MET-IHC and -FISH for possible MET-targeted therapy of MM remains to be elucidated.

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Treatment of advanced non-small cell lung cancer with driver mutations: current applications and future directions

et al. 2023

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Targeted Therapy Approaches for MET Abnormalities in Non-Small Cell Lung Cancer

Cited by 20 publications

References 64 publications

Met-signaling Controls Dendritic Cell Migration by Regulating Podosome Formation and Function

Met-signaling Controls Dendritic Cell Migration by Regulating Podosome Formation and Function

Correlation of MET-Receptor Overexpression with MET Gene Amplification and Patient Outcome in Malignant Mesothelioma

Treatment of advanced non-small cell lung cancer with driver mutations: current applications and future directions

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