Genetic events that limit the efficacy of MEK and RTK inhibitor therapies in a mouse model of KRAS-driven pancreatic cancer.
Mutated KRAS (KRAS*) is a fundamental driver in the majority of pancreatic ductal adenocarcinomas (PDAC). Using an inducible mouse model of KRAS*-driven PDAC, we compared KRAS* genetic extinction with pharmacologic inhibition of MEK1 in tumor spheres and in vivo. KRAS* ablation blocked proliferation and induced apoptosis, whereas MEK1 inhibition exerted cytostatic effects. Proteomic analysis evidenced that MEK1 inhibition was accompanied by a sustained activation of the PI3K-AKT-MTOR pathway and by the activation of AXL, PDGFRa, and HER1-2 receptor tyrosine kinases (RTK) expressed in a large proportion of human PDAC samples analyzed. Although single inhibition of each RTK alone or plus MEK1 inhibitors was ineffective, a combination of inhibitors targeting all three coactivated RTKs and MEK1 was needed to inhibit proliferation and induce apoptosis in both mouse and human low-passage PDAC cultures. Importantly, constitutive AKT activation, which may mimic the fraction of AKT2-amplified PDAC, was able to bypass the induction of apoptosis caused by KRAS* ablation, highlighting a potential inherent resistance mechanism that may inform the clinical application of MEK inhibitor therapy. This study suggests that combinatorial-targeted therapies for pancreatic cancer must be informed by the activation state of each putative driver in a given treatment context. In addition, our work may offer explanative and predictive power in understanding why inhibitors of EGFR signaling fail in PDAC treatment and how drug resistance mechanisms may arise in strategies to directly target KRAS.
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. gdraetta@mdanderson.org PFPettazzoni@MDAnderson.org.
Piergiorgio
P
Pettazzoni
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Andrea
A
Viale
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Parantu
P
Shah
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Alessandro
A
Carugo
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Haoqiang
H
Ying
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Huamin
H
Wang
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Giannicola
G
Genovese
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Sahil
S
Seth
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
Rosalba
R
Minelli
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Tessa
T
Green
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Emmet
E
Huang-Hobbs
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Denise
D
Corti
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Nora
N
Sanchez
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Luigi
L
Nezi
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Matteo
M
Marchesini
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Avnish
A
Kapoor
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Wantong
W
Yao
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Maria E Di
ME
Francesco
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Alessia
A
Petrocchi
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Angela K
AK
Deem
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
Kenneth
K
Scott
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Simona
S
Colla
Department of System Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Gordon B
GB
Mills
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jason B
JB
Fleming
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Timothy P
TP
Heffernan
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Philip
P
Jones
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Carlo
C
Toniatti
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Ronald A
RA
DePinho
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas. gdraetta@mdanderson.org PFPettazzoni@MDAnderson.org.
Giulio F
GF
Draetta
D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology
D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D020794:Receptor Protein-Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; C546843:mTOR protein, mouse; C495971:Hras protein, mouse