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Review
. 2016 Sep 6;1(5):e000076.
doi: 10.1136/esmoopen-2016-000076. eCollection 2016.

KRAS-driven lung adenocarcinoma: combined DDR1/Notch inhibition as an effective therapy

Chiara Ambrogio  1 , Ernest Nadal  2 , Alberto Villanueva  3 , Gonzalo Gómez-López  4 , Timothy P Cash  5 , Mariano Barbacid  6 , David Santamaría  6
Affiliations
Review

KRAS-driven lung adenocarcinoma: combined DDR1/Notch inhibition as an effective therapy

Chiara Ambrogio et al. ESMO Open. .

Abstract

Understanding the early evolution of cancer heterogeneity during the initial steps of tumorigenesis can uncover vulnerabilities of cancer cells that may be masked at later stages. We describe a comprehensive approach employing gene expression analysis in early lesions to identify novel therapeutic targets and the use of mouse models to test synthetic lethal drug combinations to treat human Kirsten rat sarcoma viral oncogene homologue (KRAS)-driven lung adenocarcinoma.

Keywords: KRAS; Lung adenocarcinoma.

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Conflict of interest statement

Conflicts of Interest: None declared.

Figures

Figure 1
Figure 1
Early lesion analysis to identify potential targets for therapeutic intervention. (A). KrasG12V-driven early lung lesions (≤500 cells) were microdissected and analysed by standard Affymetrix technology. Tumour signatures clustered in two distinct groups, one of which resembled normal lung alveolar cells (H1) and the other one aggressive murine and human lung adenocarcinoma (H2). The top-scoring gene of the H2 signature was the Discoidin Domain Receptor 1 (DDR1). (B). KrasG12V-driven lung tumours (10 months after Ad-Cre infection) were isolated and analysed by standard Affymetrix technology. Tumour signatures clustered in two distinct groups, T1 and T2. H2 signature was diluted in the T2 signature. (C). KrasG12V;Ddr1−/− mice survived longer and have reduced tumour size/number compared to control KrasG12V; Ddr1+/+ mice.
Figure 2
Figure 2
Therapeutic validation in orthotopic lung PDX. (A). Biopsies from patients carrying KRAS-mutant;TP53-deficient lung adenocarcinomas were orthotopically implanted in Crl:NU-Foxn1nu mice and subjected to treatment with either vehicle, cisplatin/paclitaxel chemotherapy or dasatinib/demcizumab. Positron emission tomography (PET) follow-up demonstrated a better response when compared with chemotherapy. CD31 immunostaining showed a substantial decrease of the endothelial compartment in tumours subjected to the combined therapy. (B). Percentages of alteration frequencies identified in different NSCLC studies obtained from the TCGA database (http://www.cbioportal.org). Red=gene amplification; green=mutation. PDX, patient-derived xenograft; NSCLC, non-small cell lung carcinoma.
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