Precision oncology has made significant progress in identifying actionable aberrations in tumors and matching them to specific therapies, resulting in improved patient outcomes. However, as not all patients respond, it remains a challenge to select patients to benefit from genetically matched therapies. Organoids, stem cell-based three-dimensional cell cultures from patients, can be used to predict drug responses.
Researchers from the department of medical oncology and experimental urology recently published an example of this approach in Oral Oncology. Organoids from a patient with a rare form of salivary gland cancer driven by a specific ETV6-NTRK3 gene fusion were cultured and subjected to a specific TRK signaling inhibitor, larotrectinib. The patient who also received this drug responded very well to this treatment, as the macroscopic metastasis rapidly disappeared.
Unfortunately, the organoids did not respond to larotrectinib. Although genomic mimicry was evident in pre-larotrectinib organoids, transcriptomic and phenotypic divergence was observed. For example, despite the presence of the ETV6-NTRK3 transcript, the organoids did not express TRK proteins. We could find no evidence that contamination of tumor tissue with benign cells could explain the discrepant tumor and organoid phenotypes. Another explanation could be that growth factors in the organoid culture medium influence the phenotype of the organoids. Such factors may induce survival pathways that bypass the need for NTRK signaling, thereby possibly explaining the lack of larotrectinib sensitivity.
This study emphasizes the importance of thorough characterization of organoids and organoid culture conditions before extrapolating in vitro drug reactions to possible clinical responses.
Lassche G, van Engen-van Grunsven ACH, van Hooij O, Aalders TW, Am Weijers J, Cocco E, et al. Precision oncology using organoids of a secretory carcinoma of the salivary gland treated with TRK-inhibitors. Oral Oncol. 2023;137:106297.
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