Reference Detail

Ref Type

Journal Article

PMID

(37463056)

Authors

Singh H, Keller RB, Kapner KS, Dilly J, Raghavan S, Yuan C, Cohen EF, Tolstorukov M, Andrews E, Brais LK, da Silva A, Perez K, Rubinson DA, Surana R, Giannakis M, Ng K, Clancy TE, Yurgelun MB, Schlechter BL, Clark JW, Shapiro GI, Rosenthal MH, Hornick JL, Nardi V, Li YY, Gupta H, Cherniack AD, Meyerson M, Cleary JM, Nowak JA, Wolpin BM, Aguirre AJ

Title

Oncogenic Drivers and Therapeutic Vulnerabilities in KRAS Wild-Type Pancreatic Cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	29	22	2023 Nov 14	4627-4643	Clin Cancer Res

URL

Abstract Text

Approximately 8% to 10% of pancreatic ductal adenocarcinomas (PDAC) do not harbor mutations in KRAS. Understanding the unique molecular and clinical features of this subset of pancreatic cancer is important to guide patient stratification for clinical trials of molecularly targeted agents.We analyzed a single-institution cohort of 795 exocrine pancreatic cancer cases (including 785 PDAC cases) with a targeted multigene sequencing panel and identified 73 patients (9.2%) with KRAS wild-type (WT) pancreatic cancer.Overall, 43.8% (32/73) of KRAS WT cases had evidence of an alternative driver of the MAPK pathway, including BRAF mutations and in-frame deletions and receptor tyrosine kinase fusions. Conversely, 56.2% of cases did not harbor a clear MAPK driver alteration, but 29.3% of these MAPK-negative KRAS WT cases (12/41) demonstrated activating alterations in other oncogenic drivers, such as GNAS, MYC, PIK3CA, and CTNNB1. We demonstrate potent efficacy of pan-RAF and MEK inhibition in patient-derived organoid models carrying BRAF in-frame deletions. Moreover, we demonstrate durable clinical benefit of targeted therapy in a patient harboring a KRAS WT tumor with a ROS1 fusion. Clinically, patients with KRAS WT tumors were significantly younger in age of onset (median age: 62.6 vs. 65.7 years; P = 0.037). SMAD4 mutations were associated with a particularly poor prognosis in KRAS WT cases.This study defines the genomic underpinnings of KRAS WT pancreatic cancer and highlights potential therapeutic avenues for future investigation in molecularly directed clinical trials. See related commentary by Kato et al., p. 4527.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF N486_P490del	pancreatic ductal adenocarcinoma	sensitive	Trametinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, a pancreatic ductal adenocarcinoma patient-derived organoid model harboring BRAF N486_P490del was sensitive to treatment with Mekinist (trametinib) in culture, demonstrating decreased cell viability (PMID: 37463056).	37463056
BRAF N486_P490del	pancreatic ductal adenocarcinoma	sensitive	Ulixertinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, a pancreatic ductal adenocarcinoma patient-derived organoid model harboring BRAF N486_P490del was sensitive to treatment with Ulixertinib (BVD-523) in culture, demonstrating decreased cell viability (PMID: 37463056).	37463056