Investigating the Retained Inhibitory Effect of Cobimetinib against p.P124L Mutated MEK1: A Combined Liquid Biopsy and in Silico Approach

Catoni, Cristina; Poggiana, Cristina; Facchinetti, Antonella; Pigozzo, Jacopo; Piccin, Luisa; Chiarion-Sileni, Vanna; Rosato, Antonio; Minervini, Giovanni; Scaini, Maria Chiara

doi:10.3390/cancers14174153

Cited by 4 publications

(1 citation statement)

References 57 publications

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“…The SureSelect All-In-One NGS custom panel (Agilent Technologies; see [66] for panel specifics) was performed on both the primary/metastatic tumor tissue samples and plasma-/pleural effusion-derived ctDNA. Alignment and variant calling were assessed through the SureCall software v.4.2 (Agilent Technologies), with interpretation and prioritization by Alissa Interpret Analysis Software v.5.3.4 (Agilent Technologies).…”

Section: Sample Collection Tissue and Cfdna Analysesmentioning

confidence: 99%

Molecular Modeling Unveils the Effective Interaction of B-RAF Inhibitors with Rare B-RAF Insertion Variants

Scaini,

Piccin,

Bassani

et al. 2023

IJMS

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The Food and Drug Administration (FDA) has approved MAPK inhibitors as a treatment for melanoma patients carrying a mutation in codon V600 of the BRAF gene exclusively. However, BRAF mutations outside the V600 codon may occur in a small percentage of melanomas. Although these rare variants may cause B-RAF activation, their predictive response to B-RAF inhibitor treatments is still poorly understood. We exploited an integrated approach for mutation detection, tumor evolution tracking, and assessment of response to treatment in a metastatic melanoma patient carrying the rare p.T599dup B-RAF mutation. He was addressed to Dabrafenib/Trametinib targeted therapy, showing an initial dramatic response. In parallel, in-silico ligand-based homology modeling was set up and performed on this and an additional B-RAF rare variant (p.A598_T599insV) to unveil and justify the success of the B-RAF inhibitory activity of Dabrafenib, showing that it could adeptly bind both these variants in a similar manner to how it binds and inhibits the V600E mutant. These findings open up the possibility of broadening the spectrum of BRAF inhibitor-sensitive mutations beyond mutations at codon V600, suggesting that B-RAF V600 WT melanomas should undergo more specific investigations before ruling out the possibility of targeted therapy.

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Section: Sample Collection Tissue and Cfdna Analysesmentioning

confidence: 99%

Molecular Modeling Unveils the Effective Interaction of B-RAF Inhibitors with Rare B-RAF Insertion Variants

Scaini,

Piccin,

Bassani

et al. 2023

IJMS

Self Cite

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Targeted therapy

De¹

2023

Medicines for Cancer

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A multiparameter liquid biopsy approach allows to track melanoma dynamics and identify early treatment resistance

Scaini,

Catoni,

Poggiana

et al. 2024

npj Precis. Onc.

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Melanoma heterogeneity is a hurdle in metastatic disease management. Although the advent of targeted therapy has significantly improved patient outcomes, the occurrence of resistance makes monitoring of the tumor genetic landscape mandatory. Liquid biopsy could represent an important biomarker for the real-time tracing of disease evolution. Thus, we aimed to correlate liquid biopsy dynamics with treatment response and progression by devising a multiplatform approach applied to longitudinal melanoma patient monitoring. We conceived an approach that exploits Next Generation Sequencing (NGS) and droplet digital PCR, as well as the FDA-cleared platform CellSearch, to analyze circulating tumor DNA (ctDNA) trend and circulating melanoma cell (CMC) count, together with their customized genetic and copy number variation analysis. The approach was applied to 17 stage IV melanoma patients treated with BRAF/MEK inhibitors, followed for up to 28 months. BRAF mutations were detected in the plasma of 82% of patients. Single nucleotide variants known or suspected to confer resistance were identified in 70% of patients. Moreover, the amount of ctDNA, both at baseline and during response, correlated with the type and duration of the response itself, and the CMC count was confirmed to be a prognostic biomarker. This work provides proof of principle of the power of this approach and paves the way for a validation study aimed at evaluating early ctDNA-guided treatment decisions in stage IV melanoma. The NGS-based molecular profile complemented the analysis of ctDNA trend and, together with CMC analysis, revealed to be useful in capturing tumor evolution.

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Investigating the Retained Inhibitory Effect of Cobimetinib against p.P124L Mutated MEK1: A Combined Liquid Biopsy and in Silico Approach

Cited by 4 publications

References 57 publications

Molecular Modeling Unveils the Effective Interaction of B-RAF Inhibitors with Rare B-RAF Insertion Variants

Molecular Modeling Unveils the Effective Interaction of B-RAF Inhibitors with Rare B-RAF Insertion Variants

Targeted therapy

A multiparameter liquid biopsy approach allows to track melanoma dynamics and identify early treatment resistance

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