title: Endoscopic ultrasound-guided fine-needle aspirate-derived preclinical pancreatic cancer models reveal panitumumab sensitivity in KRAS wild-type tumors.
abstract: Pancreatic cancer (PC) is largely refractory to existing therapies used in unselected patient trials, thus emphasizing the pressing need for new approaches for patient selection in personalized medicine. KRAS mutations occur in 90% of PC patients and confer resistance to epidermal growth factor receptor (EGFR) inhibitors (e.g., panitumumab), suggesting that KRAS wild-type PC patients may benefit from targeted panitumumab therapy. Here, we use tumor tissue procured by endoscopic ultrasound-guided fine-needle aspirate (EUS-FNA) to compare the in vivo sensitivity in patient-derived xenografts (PDXs) of KRAS wild-type and mutant PC tumors to panitumumab, and to profile the molecular signature of these tumors in patients with metastatic or localized disease. Specifically, RNASeq of EUS-FNA-derived tumor RNA from localized (n = 20) and metastatic (n = 20) PC cases revealed a comparable transcriptome profile. Screening the KRAS mutation status of tumor genomic DNA obtained from EUS-FNAs stratified PC patients into either KRAS wild-type or mutant cohorts, and the engraftment of representative KRAS wild-type and mutant EUS-FNA tumor samples into NOD/SCID mice revealed that the growth of KRAS wild-type, but not mutant, PDXs was selectively suppressed with panitumumab. Furthermore, in silico transcriptome interrogation of The Cancer Genome Atlas (TCGA)-derived KRAS wild-type (n = 38) and mutant (n = 132) PC tumors revealed 391 differentially expressed genes. Taken together, our study validates EUS-FNA for the application of a novel translational pipeline comprising KRAS mutation screening and PDXs, applicable to all PC patients, to evaluate personalized anti-EGFR therapy in patients with KRAS wild-type tumors.
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, 3168, Australia.|Department of Molecular Translational Science, School of Clinical Sciences, Monash University, Clayton, VIC, 3168, Australia.
authors.forename: William
authors.initials: W
authors.lastname: Berry
authors.affiliation: Genetics and Molecular Pathology Laboratory, Monash Health, Clayton, VIC, 3168, Australia.|Centre for Cancer Research, Hudson Institute of Medical Research, Monash University, Clayton, VIC, 3168, Australia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Algar
authors.affiliation: Department of Anatomical Pathology, Monash Health, Clayton, VIC, 3168, Australia.
authors.forename: Beena
authors.initials: B
authors.lastname: Kumar
authors.affiliation: Department of Gastroenterology, Monash Health, Clayton, VIC, 3168, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Desmond
authors.affiliation: Department of Gastroenterology, Monash Health, Clayton, VIC, 3168, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Swan
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, 3168, Australia.|Department of Molecular Translational Science, School of Clinical Sciences, Monash University, Clayton, VIC, 3168, Australia.
authors.forename: Brendan J
authors.identifier: 0000-0002-7552-4656
authors.initials: BJ
authors.lastname: Jenkins
authors.affiliation: Department of Surgery (School of Clinical Sciences at Monash Health), Monash University, Clayton, VIC, 3800, Australia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Croagh
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D061765:Endoscopic Ultrasound-Guided Fine Needle Aspiration; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077544:Panitumumab; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D000077544:Panitumumab; D016283:Proto-Oncogene Proteins p21(ras)
keywords: EUS-FNA; KRAS; RNASeq; pancreatic cancer; panitumumab; patient-derived xenograft