Reference Detail

Ref Type Journal Article
PMID (26855149)
Authors Ambrogio C, Gómez-López G, Falcone M, Vidal A, Nadal E, Crosetto N, Blasco RB, Fernández-Marcos PJ, Sánchez-Céspedes M, Ren X, Wang Z, Ding K, Hidalgo M, Serrano M, Villanueva A, Santamaría D, Barbacid M
Title Combined inhibition of DDR1 and Notch signaling is a therapeutic strategy for KRAS-driven lung adenocarcinoma.
Journal Nature medicine
Vol 22
Issue 3
Date 2016 Mar
URL
Abstract Text Patients with advanced Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant lung adenocarcinoma are currently treated with standard chemotherapy because of a lack of efficacious targeted therapies. We reasoned that the identification of mediators of Kras signaling in early mouse lung hyperplasias might bypass the difficulties that are imposed by intratumor heterogeneity in advanced tumors, and that it might unveil relevant therapeutic targets. Transcriptional profiling of Kras(G12V)-driven mouse hyperplasias revealed intertumor diversity with a subset that exhibited an aggressive transcriptional profile analogous to that of advanced human adenocarcinomas. The top-scoring gene in this profile encodes the tyrosine kinase receptor DDR1. The genetic and pharmacological inhibition of DDR1 blocked tumor initiation and tumor progression, respectively. The concomitant inhibition of both DDR1 and Notch signaling induced the regression of KRAS;TP53-mutant patient-derived lung xenografts (PDX) with a therapeutic efficacy that was at least comparable to that of standard chemotherapy. Our data indicate that the combined inhibition of DDR1 and Notch signaling could be an effective targeted therapy for patients with KRAS-mutant lung adenocarcinoma.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KRAS G12V TP53 del lung cancer sensitive 7RH + LY411575 Preclinical Actionable In a preclinical study, 7RH and LY411575 combination treatment induced apoptosis in KRAS G12V-driven animal models of lung cancer with TP53 knockout background (PMID: 26855149). 26855149
KRAS G12D TP53 S127Y lung adenocarcinoma sensitive Dasatinib + Demcizumab Preclinical - Pdx Actionable In a preclinical study, combination of Sprycel (dasatinib) and Demcizumab (OMP-21M18) treatment resulted in durable tumor inhibition in patient-derived animal models of lung adenocarcinoma harboring KRAS G12D and TP53 S127Y (PMID: 26855149). 26855149
KRAS G12V TP53 del lung cancer resistant 7RH Preclinical Actionable In a preclinical study, 7RH treatment had no effect on tumor cell apoptosis in KRAS G12V-driven animal models of lung cancer with TP53 knockout background (PMID: 26855149). 26855149
KRAS G12R TP53 R248L lung adenocarcinoma sensitive Dasatinib + Demcizumab Preclinical - Pdx Actionable In a preclinical study, combination of Sprycel (dasatinib) and Demcizumab (OMP-21M18) treatment resulted in durable tumor inhibition in patient-derived animal models of lung adenocarcinoma harboring KRAS G12R and TP53 R248L (PMID: 26855149). 26855149
KRAS G12V lung cancer sensitive 7RH + LY411575 Preclinical Actionable In a preclinical study, 7RH and LY411575 combination treatment resulted in additive effect on apoptosis in KRAS G12V-driven animal models of lung cancer (PMID: 26855149). 26855149