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Genomic studies are revolutionizing clinical oncology, but bridging the lab and the bedside requires the ability to efficiently interrogate rare genetic lesions in unexpected pathological settings using preclinical models. Oncogenes can exhibit intrinsic drug resistance to targeted therapy in different cells of origin, adding complexity to clinical interpretations of genomic findings. Here, we capitalize on the flexibility of engineered cell systems to rapidly profile known multi-kinase inhibitors that harbor rearranged during transfection (RET) kinase activity across multiple RET fusions. Identifying ponatinib as the most potent RET inhibitor tested, we used ponatinib to gauge therapeutic responsiveness in RET fusion-positive patient-derived xenograft (PDX) models. Using a genomics guided outlier approach, we identified 4 RET fusion PDX models with 3 different fusion partners (KIF5B, CCDC6, and NCOA4) in both non-small cell lung cancer and colorectal cancer. By comparing ponatinib activity in RET fusion-positive and RET fusion-negative PDX models alongside a standard of care chemotherapeutic agent, we show that RET fusions in colorectal tumors are therapeutically responsive to RET inhibition. Finally, we suggest that coupling engineered cell systems and genomics guided PDX model selection provides a rapid workflow to triage rare genomics findings.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6049858 | PMC |
http://dx.doi.org/10.18632/oncotarget.25664 | DOI Listing |
Neoplasia
December 2024
Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan.
Leptomeningeal metastasis (LM) is a challenging complication of non-small cell lung cancer (NSCLC). Cerebrospinal fluid (CSF) cell-free DNA (cfDNA) analysis using next-generation sequencing (NGS) offers insights into resistance mechanisms and potential treatment strategies. We conducted a study from February 2022 to April 2023 involving patients from five hospitals in Taiwan who had recurrent or advanced NSCLC with LM.
View Article and Find Full Text PDFTher Adv Med Oncol
December 2024
Medical Oncology Department, Hospital Clinic of Barcelona, Calle Villarroel 170, Barcelona 08036, Spain.
Background: While targeted therapies have transformed the treatment landscape of oncogene-addicted non-small cell lung cancer (NSCLC), the influence of sex on treatment outcomes remains insufficiently understood.
Objectives: This systematic review aimed to investigate the impact of sex on clinical outcomes in patients with NSCLC harboring driver fusions treated with targeted therapies enrolled in clinical trials.
Data Sources And Methods: A comprehensive literature search was conducted using PubMed, Embase, and relevant conference abstracts to identify phase III randomized and early clinical trials that reported sex-specific data, including progression-free survival (PFS), overall survival (OS), overall response rate, and adverse events (AEs), in patients with fusion-positive NSCLC treated with tyrosine kinase inhibitors (TKIs).
Oral Oncol
December 2024
Department of Thyroid Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China. Electronic address:
Background: Locally advanced papillary thyroid carcinoma (PTC) with RET fusion-positive poses significant challenges for surgical resection due to tumor invasion into critical structures. Neoadjuvant targeted therapies are a promising approach to reduce the tumor burden and improve the resectability. Selperctinib, a RET kinase inhibitor, has been approved for the treatment of advanced or metastatic RET-altered thyroid cancer.
View Article and Find Full Text PDFJ Oncol Pharm Pract
December 2024
Michigan Medicine, Clinical Pharmacist Specialist, Inpatient Hematology, University of Michigan, Ann Arbor, MI, USA.
Introduction: Mutated rearranged during transfection (RET) kinase is found in approximately 1-2% non-small-cell lung cancer (NSCLC) patients. These patients are typically younger, non-smokers, and have non-squamous histology. Pralsetinib is a novel RET inhibitor that showed promising efficacy and tolerability in the ARROW trial.
View Article and Find Full Text PDFMed
December 2024
Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA; WIN Consortium, Paris, France; University of Nebraska, Omaha, NE, USA. Electronic address:
Tumor-agnostic US Food and Drug Administration approvals are transforming oncology. They include larotrectinib/entrectinib/repotrectinib (NTRK fusions), selpercatinib (RET fusions), dabrafenib/trametinib (BRAF mutations), pembrolizumab/dostarlimab (microsatellite instability), pembrolizumab (high tumor mutational burden), and trastuzumab deruxtecan (HER2 3+ expression) (all solid cancers). Pemigatinib is approved for FGFR1-rearranged myeloid/lymphoid neoplasms.
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