MET Exon 14 Skipping and Novel Actionable Variants: Diagnostic and Therapeutic Implications in Latin American Non-Small-Cell Lung Cancer Patients

Targeted therapy indications for actionable variants in non-small-cell lung cancer (NSCLC) have primarily been studied in Caucasian populations, with limited data on Latin American patients. This study utilized a 52-genes next-generation sequencing (NGS) panel to analyze 1560 tumor biopsies from NSCLC patients in Chile, Brazil, and Peru. The RNA sequencing reads and DNA coverage were correlated to improve the detection of the actionable MET exon 14 skipping variant (METex14). The pathogenicity of MET variants of uncertain significance (VUSs) was assessed using bioinformatic methods, based on their predicted driver potential. The effects of the predicted drivers VUS T992I and H1094Y on c-MET signaling activation, proliferation, and migration were evaluated in HEK293T, BEAS-2B, and H1993 cell lines. Subsequently, c-Met inhibitors were tested in 2D and 3D cell cultures, and drug affinity was determined using 3D structure simulations. The prevalence of MET variants in the South American cohort was 8%, and RNA-based diagnosis detected 27% more cases of METex14 than DNA-based methods. Notably, 20% of METex14 cases with RNA reads below the detection threshold were confirmed using DNA analysis. The novel actionable T992I and H1094Y variants induced proliferation and migration through c-Met/Akt signaling. Both variants showed sensitivity to crizotinib and savolitinib, but the H1094Y variant exhibited reduced sensitivity to capmatinib. These findings highlight the importance of RNA-based METex14 diagnosis and reveal the drug sensitivity profiles of novel actionable MET variants from an understudied patient population.

Project(s)

UNCOVERING NOVEL DRIVER MUTATIONS IN NON-SMALL CELL LUNG CANCER FROM CHILE, BRAZIL, AND PERU PATIENTS

Landscape of clinically actionable cancer genes: towards precision oncology in Chile

Subjects

c-met inhibitors

;

met exon 14 skipping

;

next-generation sequencing

;

non-small-cell lung cancer

;

novel actionable variants

;

capmatinib

;

crizotinib

;

dna

;

protein kinase b

;

rna

;

savolitinib

;

scatter factor receptor

;

akt signaling

;

article

;

autophosphorylation

;

beas-2b cell line

;

binding affinity

;

biological trait

;

brazil

;

cell migration

;

cell proliferation

;

cell survival

;

chile

;

cohort analysis

;

controlled study

;

diagnostic value

;

dna determination

;

drug protein binding

;

drug sensitivity

;

embryo

;

enzyme activation

;

exon skipping

;

gene frequency

;

gene fusion

;

genetic variability

;

hek293t cell line

;

high throughput sequencing

;

human

;

human cell

;

ic50

;

in vitro study

;

indel mutation

;

major clinical study

;

missense mutation

;

molecular docking

;

molecular dynamics

;

molecular interaction

;

molecular model

;

mutational analysis

;

nci-h1993 cell line

;

non small cell lung cancer

;

nonsense mutation

;

peru

;

prevalence

;

protein expression

;

protein phosphorylation

;

rna sequencing

;

sequence alignment

;

simulation

;

single nucleotide polymorphism

;

south american

;

splicing defect

;

three dimensional cell culture

;

tumor biopsy