Dataset Information

Patient-derived cell-based pharmacogenomic assessment to unveil underlying resistance mechanisms and novel therapeutics for advanced lung cancer.

ABSTRACT:

Background

A pharmacogenomic platform using patient-derived cells (PDCs) was established to identify the underlying resistance mechanisms and tailored treatment for patients with advanced or refractory lung cancer.

Methods

Drug sensitivity screening and multi-omics datasets were acquired from lung cancer PDCs (n = 102). Integrative analysis was performed to explore drug candidates according to genetic variants, gene expression, and clinical profiles.

Results

PDCs had genomic characteristics resembled with those of solid lung cancer tissues. PDC molecular subtyping classified patients into four groups: (1) inflammatory, (2) epithelial-to-mesenchymal transition (EMT)-like, (3) stemness, and (4) epithelial growth factor receptor (EGFR)-dominant. EGFR mutations of the EMT-like subtype were associated with a reduced response to EGFR-tyrosine kinase inhibitor therapy. Moreover, although RB1/TP53 mutations were significantly enriched in small-cell lung cancer (SCLC) PDCs, they were also present in non-SCLC PDCs. In contrast to its effect in the cell lines, alpelisib (a PI3K-AKT inhibitor) significantly inhibited both RB1/TP53 expression and SCLC cell growth in our PDC model. Furthermore, cell cycle inhibitors could effectively target SCLC cells. Finally, the upregulation of transforming growth factor-β expression and the YAP/TAZ pathway was observed in osimertinib-resistant PDCs, predisposing them to the EMT-like subtype. Our platform selected XAV939 (a WNT-TNKS-β-catenin inhibitor) for the treatment of osimertinib-resistant PDCs. Using an in vitro model, we further demonstrated that acquisition of osimertinib resistance enhances invasive characteristics and EMT, upregulates the YAP/TAZ-AXL axis, and increases the sensitivity of cancer cells to XAV939.

Conclusions

Our PDC models recapitulated the molecular characteristics of lung cancer, and pharmacogenomics analysis provided plausible therapeutic candidates.

SUBMITTER: Yu N

PROVIDER: S-EPMC9885631 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

Patient-derived cell-based pharmacogenomic assessment to unveil underlying resistance mechanisms and novel therapeutics for advanced lung cancer.

Yu Namhee N Hwang Mihwa M Lee Youngjoo Y Song Bo Ram BR Kang Eun Hye EH Sim Hanna H Ahn Beung-Chul BC Hwang Kum Hui KH Kim Jihyun J Hong Sehwa S Kim Sunshin S Park Charny C Han Ji-Youn JY

Journal of experimental & clinical cancer research : CR 20230130 1

<h4>Background</h4>A pharmacogenomic platform using patient-derived cells (PDCs) was established to identify the underlying resistance mechanisms and tailored treatment for patients with advanced or refractory lung cancer.<h4>Methods</h4>Drug sensitivity screening and multi-omics datasets were acquired from lung cancer PDCs (n = 102). Integrative analysis was performed to explore drug candidates according to genetic variants, gene expression, and clinical profiles.<h4>Results</h4>PDCs had genomi ...[more]

PMID: 36717865

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Project description:ObjectivePharmacogenomics seeks to improve prescribing by reducing drug inefficacy/toxicity. However, views of patients during pharmacogenomic-guided care are largely unknown. We sought to understand the attitudes and perceptions of patients in an institutional implementation project and hypothesized that views would differ on the basis of experience with pharmacogenomic-guided care.MethodsTwo focus groups were conducted - one group included patients who had previously been subjected to broad pharmacogenomic genotyping with results available to physicians (pharmacogenomic group), whereas the other had not been offered genotyping (traditional care). Five domains were explored: (i) experiences with medications/side effects, (ii) understanding of pharmacogenomics, (iii) impact of pharmacogenomics on relationships with healthcare professionals, (iv) scenarios involving pharmacogenomic-guided prescribing, and (v) responses to pharmacogenomic education materials.ResultsNine pharmacogenomic and 13 traditional care participants were included. Participants in both groups agreed that pharmacogenomics could inform prescribing and help identify problem prescriptions, but expressed concerns over insurance coverage and employment discrimination. Both groups diverged on who should be permitted to access pharmacogenomic results, with some preferring access only for providers with a longstanding relationship, whereas others argued for open access. Notably, traditional care participants showed greater skepticism about how results might be used. Case scenarios and tested educational materials elicited strong desires on the part of patients for physicians to engage participants when considering pharmacogenomic-based prescribing and to utilize shared decision-making.ConclusionParticipants experiencing pharmacogenomic-guided care were more receptive toward pharmacogenomic information being used than traditional care participants. As key stakeholders in implementation, addressing patients' concerns will be important to successfully facilitate clinical dissemination.

Dataset Information

Patient-derived cell-based pharmacogenomic assessment to unveil underlying resistance mechanisms and novel therapeutics for advanced lung cancer.

Background

Methods

Results

Conclusions

Publications

Patient-derived cell-based pharmacogenomic assessment to unveil underlying resistance mechanisms and novel therapeutics for advanced lung cancer.

Similar Datasets

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