RESUMO
SrGAP3/MEGAP is a member of the Slit-Robo GAP (srGAP) family and is implicated in repulsive axon guidance and neuronal migration through Slit-Robo-mediated signal transduction. Here we describe an inhibitory role of srGAP3 on actin dynamics, specifically on lamellipodia formation. We show that the F-BAR domain localizes srGAP3 to the leading edge of cellular protrusions whereas the SH3 domain is important for focal adhesion targeting. We report on a novel srGAP3 interaction partner, lamellipodin, which localizes with srGAP3 at the leading edge. Live-cell analyses revealed that srGAP3 influences lamellipodin-evoked lamellipodial dynamics. Furthermore, we show that mouse embryonic fibroblasts derived from homozygous srGAP3-knockout embryos display an increased cell area and lamellipodia formation that can be blocked by shRNA-mediated knockdown of lamellipodin.
Assuntos
Adesões Focais/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Neuropeptídeos/metabolismo , Pseudópodes/metabolismo , Proteínas rac de Ligação ao GTP/metabolismo , Actinas/metabolismo , Sequência de Aminoácidos , Animais , Encéfalo/metabolismo , Células COS , Membrana Celular/genética , Membrana Celular/metabolismo , Tamanho Celular , Chlorocebus aethiops , Clonagem Molecular , Fibroblastos/citologia , Fibroblastos/metabolismo , Adesões Focais/genética , Proteínas Ativadoras de GTPase/genética , Células HEK293 , Humanos , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Células NIH 3T3 , Neuropeptídeos/genética , Pseudópodes/genética , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas rac de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP , Domínios de Homologia de srcRESUMO
PERLA is a global, double-blind, parallel phase II trial (NCT04581824) comparing efficacy and safety of anti-PD-1 antibodies dostarlimab and pembrolizumab, plus chemotherapy (DCT and PCT, respectively) as first-line treatment in patients with metastatic non-squamous NSCLC without known targetable genomic aberrations. Patients stratified by PD-L1 tumor proportion score and smoking status were randomized 1:1, receiving ≤35 cycles 500 mg dostarlimab or 200 mg pembrolizumab, ≤35 cycles 500 mg/m2 pemetrexed and ≤4 cycles cisplatin (75 mg/m2) or carboplatin (AUC 5 mg/ml/min) Q3W. Primary endpoint was overall response rate (ORR) (blinded independent central review). Secondary endpoints include progression-free survival (PFS) based on investigator assessment, overall survival (OS) and safety. Exploratory endpoints include ORR by PD-L1 subgroup and duration of response. PERLA met its pre-specified endpoint. ORR (n/N; 95% CI) is 45% (55/121; 36.4-54.8) for DCT and 39% (48/122; 30.6-48.6) for PCT (data cut-off: 07 July 23), numerically favoring dostarlimab in PD-L1-positive subgroups. Median PFS (months [95% CI]) is 8.8 (6.7-10.4) for DCT and 6.7 (4.9-7.1) for PCT (HR 0.70 [95% CI: 0.50-0.98]; data cut-off: 04 August 22). Median OS (months [95% CI]) is 19.4 (14.5-NR) for DCT and 15.9 (11.6-19.3) for PCT (HR 0.75 [95% CI: 0.53-1.05]) (data cut-off: 07 July 23). Safety profiles are similar between groups. In this study, DCT shows similar efficacy to PCT and demonstrates clinical efficacy as first-line treatment for patients with metastatic non-squamous NSCLC.