RESUMO
Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant persister cells (DTPs) which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling axis that promotes residual disease during oncogenic EGFR-, ALK-, and KRAS-targeted therapies. FAK-YAP signaling inhibition combined with the primary targeted therapy suppressed residual drug-tolerant cells and enhanced tumor responses. This study unveils a FAK-YAP signaling module that promotes residual disease in lung cancer and mechanism-based therapeutic strategies to improve tumor response.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares , Transdução de Sinais , Fatores de Transcrição , Proteínas de Sinalização YAP , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Sinalização YAP/metabolismo , Linhagem Celular Tumoral , Animais , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasia Residual , Camundongos , Quinase 1 de Adesão Focal/metabolismo , Quinase 1 de Adesão Focal/genética , Receptores ErbB/metabolismo , Receptores ErbB/genética , Quinase do Linfoma Anaplásico/metabolismo , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Vascular grafts are used to reconstruct congenital cardiac anomalies, redirect flow, and offer vascular access. Donor tissue, synthetic, or more recently tissue-engineered vascular grafts each carry limitations spanning compatibility, availability, durability and cost. Synthetic and tissue-engineered grafts offer the advantage of design optimization using in-silico or in-vitro modeling techniques. We focus on an in-silico parametric study to evaluate implantation configuration alternatives and surface finishing impact of a novel silicon-lined vascular graft. The model consists of a synthetic 3D-generic model of a graft connecting the internal carotid artery to the jugular vein. The flow is assumed unsteady, incompressible, and blood is modeled as a non-Newtonian fluid. A comparison of detached eddy turbulence and laminar modeling to determine the required accuracy needed found mild differences mainly dictated by the roughness level. The conduit walls are modeled as non-compliant and fixed. The shunt configurations considered, are straight and curved with varied surface roughness. Following a grid convergence study, two shunt configurations are analyzed to better understand flow distribution, peak shear locations, stagnation regions and eddy formation. The curved shunt was found to have lower peak and mean wall-shear stress, while resulting in lower flow power system and decreased power loss across the graft. The curved smooth surface shunt shows lower peak and mean wall-shear stress and lower power loss when compared to the straight shunt.
