Modeling Clinical Responses to Targeted Therapies by Patient-Derived Organoids of Advanced Lung Adenocarcinoma

Abstract

We demonstrated that in vitro drug responses in patient-derived organoids (PDOs) are correlated to clinical responses to targeted therapies in individual patients with advanced lung adenocarcinoma and PDOs can be used to identify effective anti-cancer therapies for novel molecular targets. PDOs recapitulated progression-free survival and objective responses of NSCLC patients receiving clinically approved targeted agents. PDOs also predicted activity of therapeutic strategies under clinical investigation. YUO-071 harboring an EGFR exon 19 deletion and a BRAF G464A mutation and the matching patient responded to dabrafenib/trametinib combination therapy. YUO-004 and YUO-050 harboring an EGFR L747P mutation was sensitive to afatinib, consistent with the response in the matching patient of YUO-050. Furthermore, we utilized organoids to demonstrate preclinical efficacy of poziotinib against ERBB2 exon 20 insertions and pralsetinib against RET-fusions. Our findings suggest utility of PDOs in clinical decision making and development of therapeutic strategies.

A Lung Cancer Patient Harboring a Rare Oncogenic EGFR Exon 20 V786M Mutation Responded to a Third-Generation Tyrosine Kinase Inhibitor: Case Report and Review of the Literature

“…Third-generation TKI osimertinib has also demonstrated potent activity against uncommon EGFR mutations in NSCLC ( 11 ). With the development of techniques, the clinical response of targeted drugs is also being tested in patient-derived organoids (PDOs) ( 12 ). The promise of PDOs as a patient-proximate culture system has led to great progress, with an increasing number of models emerging recently.…”

Scientific Validation and Clinical Application of Lung Cancer Organoids

“…LCOs can be used for selecting personalized medicine and predicting the drug response of patients. Cho et al showed that LCOs can predict drug responses such as progression-free survival and objective response [ 39 ]. LCOs have the potential for high-throughput drug screening [ 10 , 11 , 12 ].…”

“…Interactions with mesenchymal cells affect the differentiation and stemness of BASCs and AT2 cells [ 12 , 20 , 21 , 42 ]. For example, BASCs differentiate into alveolar lineages when cultured with endothelial cells [ 21 ], and type II cells produce alveolar spheres when cultured with fibroblasts [ 39 ]. Co-culture of type II pneumocytes and fibroblasts revealed that Wnt signaling maintains AT2 stemness and prevents differentiation to AT1 cells [ 43 ] ( Table 3 ).…”

“…In terms of success rate, generation time, genetic manipulation, and cost, LCO is a valuable tool for drug screening and predicting the drug response of patients. Organoid models can be used to detect rare genetic mutations and optimize treatment drugs [ 10 , 39 ] ( Table 4 ). Kim produced LCOs from KrasG12D or KrasG12D, p53fl/fl mice [ 54 ].…”

Anticipating EGFR Targeting in Early Stages of Lung Cancer: Leave No Stone Unturned

“…Moreover, lessons we are learning in the advanced setting may be useful for customizing the therapeutical approach according to the molecular background of the disease and its evolution over time. Although many open issues are still to be answered regarding the management of tumor heterogeneity/resistance and, in this sense, the potential room for treatment combinations at baseline or at progression [42], innovative diagnostic tools coming from the preclinical as patient-derived organoids (PDOs) may accelerate the identification and development of effective therapeutic strategies able to assist the clinical decision-making process [43]. In this light, the identification and validation of reliable predictive biomarkers represent a crucial gap to be fulfilled.…”