Identification of synergistic combination of molecular targeted agents and chemotherapy using TumorGraft3D and the Lumin Platform

The advent of targeted therapy based on advanced molecular profiling has revolutionized the way cancer patients are treated. A successful example is the use of tyrosine kinase inhibitors (TKIs) for non-small-cell lung cancer (NSCLC) and melanoma. Unfortunately, the tumor often becomes resistant to these agents after the initial therapeutic benefit. The majority of epidermal growth factor receptor (EGFR) mutations in NSCLC occur in exons 18-21 of the tyrosine kinase domain of the receptor. The T790M substitution within exon 20, is a leading contributor to resistance to first- and second-generation EGFR inhibitors in NSCLC. Osimertinib is an oral, third-generation EGFR-TKI designed to overcome T790M-driven EGFR-TKI resistance while targeting the initial EGFR-activating
mutation.

In melanoma patients, BRAF mutations occur frequently (more than 80% of cases). Vemurafenib is an FDA-approved targeted therapy for BRAF-mut melanoma. Different mechanisms characterize EGFR and BRAF acquired resistance and the knowledge of these will help develop new therapies for overcoming acquired resistance.

Champions TumorGraft3D platform utilizes multiclonal 3D tumor cultures derived from well-characterized patient-derived xenograft (PDX) models for ex vivo drug testing.

This platform adopts a unique assay with no matrix added and uses indication-specific media to allow for TumorGraft3D formation and proliferation. These are actively proliferating 3D models that faithfully recapitulate their parent PDXs and are ideal for testing single-agent and combination drug efficacy.

We employed our TumorGraft3D platform to test osimertinib in 2 NSCLC models, one EGFR-mut and one EGFR-wt, and vemurafenib in 2 BRAF-mut melanoma models. We used the Lumin Bioinformatics Pharmacology Analysis tool to evaluate the efficacy and synergistic effect of combining osimertinib and cisplatin in the EGFR-wt NSCLC TumorGraft3D model.