Molecular Characterization and Therapeutic Opportunities in KRAS Wildtype Pancreatic Ductal Adenocarcinoma.
In: Cancers, Jg. 16 (2024-05-15), Heft 10, S. 1861-1872
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Simple Summary: Pancreatic cancer is predicted to be the second-highest cause of cancer mortality in the US by 2040. It is driven by various mutations including KRAS, TP53, SMAD4, and CDKN2A. Roughly 1 in 10 patients with pancreatic cancer have wildtype KRAS (KRAS WT ). We studied 27 patients with KRAS WT to better understand their molecular characteristics and potential for precision medicine. Our findings revealed that KRAS WT PDAC is enriched with potentially treatable genetic alterations, including those affecting the MAPK pathway, DNA repair pathway, and kinase fusion genes. One of our KRAS WT PDAC patients was found to have a specific, targetable TFG-MET mutation and they responded well to treatment with a cMET inhibitor. This suggests that KRAS WT PDAC has unique genetic characteristics that could be targeted with specific treatments tailored to each patient, highlighting the importance of comprehensive genetic profiling in KRAS WT PDAC. Purpose: To investigate the molecular characteristics of and potential for precision medicine in KRAS wildtype pancreatic ductal adenocarcinoma (PDAC). Patients and Methods: We investigated 27 patients with KRAS WT PDAC at our institution. Clinical data were obtained via chart review. Tumor specimens for each subject were interrogated for somatic single nucleotide variants, insertion and deletions, and copy number variants by DNA sequencing. Gene fusions were detected from RNA-seq. A patient-derived organoid (PDO) was developed from a patient with a MET translocation and expanded ex vivo to predict therapeutic sensitivity prior to enrollment in a phase 2 clinical trial. Results: Transcriptomic analysis showed our cohort may be stratified by the relative gene expression of the KRAS signaling cascade. The PDO derived from our patient harboring a TFG-MET rearrangement was found to have in vitro sensitivity to the multi-tyrosine kinase inhibitor crizotinib. The patient was enrolled in the phase 2 SPARTA clinical trial and received monotherapy with vebrelitinib, a c-MET inhibitor, and achieved a partial and durable response. Conclusions: KRAS WT PDAC is molecularly distinct from KRAS MUT and enriched with potentially actionable genetic variants. In our study, transcriptomic profiling revealed that the KRAS signaling cascade may play a key role in KRAS WT PDAC. Our report of a KRAS WT PDAC patient with TFG-MET rearrangement who responded to a cMET inhibitor further supports the pursuit of precision oncology in this sub-population. Identification of targetable mutations, perhaps through approaches like RNA-seq, can help enable precision-driven approaches to select optimal treatment based on tumor characteristics. [ABSTRACT FROM AUTHOR]
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Titel: |
Molecular Characterization and Therapeutic Opportunities in KRAS Wildtype Pancreatic Ductal Adenocarcinoma.
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Autor/in / Beteiligte Person: | Desai, Aakash ; Xiao, Alexander H. ; Choi, Daheui ; Toruner, Merih D. ; Walden, Daniel ; Halfdanarson, Thorvardur R. ; Alberts, Steven ; McWilliams, Robert R. ; Mahipal, Amit ; Ahn, Daniel ; Babiker, Hani ; Stybayeva, Gulnaz ; Revzin, Alexander ; Kizilbash, Sani ; Adjei, Alex ; Bekaii-Saab, Tanios ; Mansfield, Aaron S. ; Carr, Ryan M. ; Ma, Wen Wee |
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Zeitschrift: | Cancers, Jg. 16 (2024-05-15), Heft 10, S. 1861-1872 |
Veröffentlichung: | 2024 |
Medientyp: | academicJournal |
ISSN: | 2072-6694 (print) |
DOI: | 10.3390/cancers16101861 |
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