TY - JOUR
T1 - KRASG12C-inhibitor-based combination therapies for pancreatic cancer
T2 - insights from drug screening
AU - Tapia Contreras, Constanza
AU - Falke, Jonas Dominik
AU - Seifert, Dana Magdalena
AU - Schneider, Carolin
AU - Krauß, Lukas
AU - Fang, Xin
AU - Müller, Denise
AU - Demirdizen, Engin
AU - Spitzner, Melanie
AU - De Oliveira, Tiago
AU - Schneeweis, Christian
AU - Gaedcke, Jochen
AU - Kaulfuß, Silke
AU - Mirzakhani, Kimia
AU - Wollnik, Bernd
AU - Conrads, Karly
AU - Beißbarth, Tim
AU - Salinas, Gabriela
AU - Hügel, Jonas
AU - Beyer, Nils
AU - Rheinländer, Sophia
AU - Sax, Ulrich
AU - Wirth, Matthias
AU - Conradi, Lena Christin
AU - Reichert, Maximilian
AU - Ellenrieder, Volker
AU - Ströbel, Philipp
AU - Ghadimi, Michael
AU - Grade, Marian
AU - Saur, Dieter
AU - Hessmann, Elisabeth
AU - Schneider, Günter
N1 - Publisher Copyright:
© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
PY - 2024
Y1 - 2024
N2 - Pancreatic ductal adenocarcinoma (PDAC) has limited treatment options, emphasizing the urgent need for effective therapies. The predominant driver in PDAC is mutated KRAS proto-oncogene, KRA, present in 90% of patients. The emergence of direct KRAS inhibitors presents a promising avenue for treatment, particularly those targeting the KRASG12C mutated allele, which show encouraging results in clinical trials. However, the development of resistance necessitates exploring potent combination therapies. Our objective was to identify effective KRASG12C-inhibitor combination therapies through unbiased drug screening. Results revealed synergistic effects with son of sevenless homolog 1 (SOS1) inhibitors, tyrosine-protein phosphatase non-receptor type 11 (PTPN11)/Src homology region 2 domain-containing phosphatase-2 (SHP2) inhibitors, and broad-spectrum multi-kinase inhibitors. Validation in a novel and unique KRASG12C-mutated patient-derived organoid model confirmed the described hits from the screening experiment. Our findings propose strategies to enhance KRASG12C-inhibitor efficacy, guiding clinical trial design and molecular tumor boards.
AB - Pancreatic ductal adenocarcinoma (PDAC) has limited treatment options, emphasizing the urgent need for effective therapies. The predominant driver in PDAC is mutated KRAS proto-oncogene, KRA, present in 90% of patients. The emergence of direct KRAS inhibitors presents a promising avenue for treatment, particularly those targeting the KRASG12C mutated allele, which show encouraging results in clinical trials. However, the development of resistance necessitates exploring potent combination therapies. Our objective was to identify effective KRASG12C-inhibitor combination therapies through unbiased drug screening. Results revealed synergistic effects with son of sevenless homolog 1 (SOS1) inhibitors, tyrosine-protein phosphatase non-receptor type 11 (PTPN11)/Src homology region 2 domain-containing phosphatase-2 (SHP2) inhibitors, and broad-spectrum multi-kinase inhibitors. Validation in a novel and unique KRASG12C-mutated patient-derived organoid model confirmed the described hits from the screening experiment. Our findings propose strategies to enhance KRASG12C-inhibitor efficacy, guiding clinical trial design and molecular tumor boards.
KW - KRAS
KW - SHP2
KW - SOS1
KW - pancreatic cancer
UR - http://www.scopus.com/inward/record.url?scp=85203440800&partnerID=8YFLogxK
U2 - 10.1002/1878-0261.13725
DO - 10.1002/1878-0261.13725
M3 - Article
AN - SCOPUS:85203440800
SN - 1574-7891
JO - Molecular Oncology
JF - Molecular Oncology
ER -
