EMT, Stemness, and Drug Resistance in Biological Context: A 3D Tumor Tissue/In Silico Platform for Analysis of Combinatorial Treatment in NSCLC with Aggressive KRAS-Biomarker Signatures

Author:

Peindl Matthias,Göttlich Claudia,Crouch Samantha,Hoff Niklas,Lüttgens Tamara,Schmitt Franziska,Pereira Jesús Guillermo NievesORCID,May Celina,Schliermann Anna,Kronenthaler Corinna,Cheufou Danjouma,Reu-Hofer Simone,Rosenwald Andreas,Weigl Elena,Walles ThorstenORCID,Schüler JuliaORCID,Dandekar ThomasORCID,Nietzer Sarah,Dandekar Gudrun

Abstract

Epithelial-to-mesenchymal transition (EMT) is discussed to be centrally involved in invasion, stemness, and drug resistance. Experimental models to evaluate this process in its biological complexity are limited. To shed light on EMT impact and test drug response more reliably, we use a lung tumor test system based on a decellularized intestinal matrix showing more in vivo-like proliferation levels and enhanced expression of clinical markers and carcinogenesis-related genes. In our models, we found evidence for a correlation of EMT with drug resistance in primary and secondary resistant cells harboring KRASG12C or EGFR mutations, which was simulated in silico based on an optimized signaling network topology. Notably, drug resistance did not correlate with EMT status in KRAS-mutated patient-derived xenograft (PDX) cell lines, and drug efficacy was not affected by EMT induction via TGF-β. To investigate further determinants of drug response, we tested several drugs in combination with a KRASG12C inhibitor in KRASG12C mutant HCC44 models, which, besides EMT, display mutations in P53, LKB1, KEAP1, and high c-MYC expression. We identified an aurora-kinase A (AURKA) inhibitor as the most promising candidate. In our network, AURKA is a centrally linked hub to EMT, proliferation, apoptosis, LKB1, and c-MYC. This exemplifies our systemic analysis approach for clinical translation of biomarker signatures.

Funder

BMBF

Bavarian Research Foundation

Publisher

MDPI AG

Subject

Cancer Research,Oncology

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