Resistance to dual blockade of the kinases PI3K and mTOR in KRAS-mutant colorectal cancer models results in combined sensitivity to inhibition of the receptor tyrosine kinase EGFR.
Targeted blockade of aberrantly activated signaling pathways is an attractive therapeutic strategy for solid tumors, but drug resistance is common. KRAS is a frequently mutated gene in human cancer but remains a challenging clinical target. Inhibitors against KRAS signaling mediators, namely, PI3K (phosphatidylinositol 3-kinase) and mTOR (mechanistic target of rapamycin), have limited clinical efficacy as single agents in KRAS-mutant colorectal cancer (CRC). We investigated potential bypass mechanisms to PI3K/mTOR inhibition in KRAS-mutant CRC. Using genetically engineered mouse model cells that had acquired resistance to the dual PI3K/mTOR small-molecule inhibitor PF-04691502, we determined with chemical library screens that inhibitors of the ERBB [epidermal growth factor receptor (EGFR)] family restored the sensitivity to PF-04691502. Although EGFR inhibitors alone have limited efficacy in reducing KRAS-mutant tumors, we found that PF-04691502 induced the abundance, phosphorylation, and activity of EGFR, ERBB2, and ERBB3 through activation of FOXO3a (forkhead box O 3a), a transcription factor inhibited by the PI3K to AKT pathway. PF-04691502 also induced a stem cell-like gene expression signature. KRAS-mutant patient-derived xenografts from mice treated with PF-04691502 had a similar gene expression signature and exhibited increased EGFR activation, suggesting that this drug-induced resistance mechanism may occur in patients. Combination therapy with dacomitinib (a pan-ERBB inhibitor) restored sensitivity to PF-04691502 in drug-resistant cells in culture and induced tumor regression in drug-resistant allografts in mice. Our findings suggest that combining PI3K/mTOR and EGFR inhibitors may improve therapeutic outcome in patients with KRAS-mutant CRC.
Oncology Research Unit, Pfizer Global Research and Development, San Diego, CA 92121, USA. esmartin.phd@gmail.com petebelmont@gmail.com.
Peter J
PJ
Belmont
Oncology Research Unit, Pfizer Global Research and Development, San Diego, CA 92121, USA.
Ping
P
Jiang
Departments of Radiation Oncology and Medical Biophysics, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.
Trevor D
TD
McKee
Oncology Research Unit, Pfizer Global Research and Development, San Diego, CA 92121, USA.
Tao
T
Xie
Oncology Research Unit, Pfizer Global Research and Development, San Diego, CA 92121, USA.
Jason
J
Isaacson
Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
Nicole E
NE
Baryla
Division of Gastroenterology, Department of Medicine, Tufts Medical Center, Boston, MA 02111, USA.
Jatin
J
Roper
Division of Gastroenterology, Department of Medicine, Tufts Medical Center, Boston, MA 02111, USA.
Mark J
MJ
Sinnamon
Oncology Research Unit, Pfizer Global Research and Development, San Diego, CA 92121, USA.
Nathan V
NV
Lee
Oncology Research Unit, Pfizer Global Research and Development, San Diego, CA 92121, USA.
Julie L C
JL
Kan
Oncology Research Unit, Pfizer Global Research and Development, San Diego, CA 92121, USA.
Oivin
O
Guicherit
Departments of Radiation Oncology and Medical Biophysics, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada. Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
Bradly G
BG
Wouters
University Health Network, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
Catherine A
CA
O'Brien
Oncology Research Unit, Pfizer Global Research and Development, San Diego, CA 92121, USA.
David
D
Shields
Oncology Research Unit, Pfizer Global Research and Development, San Diego, CA 92121, USA.
Peter
P
Olson
Oncology Research Unit, Pfizer Global Research and Development, San Diego, CA 92121, USA.
Todd
T
VanArsdale
Oncology Research Unit, Pfizer Global Research and Development, San Diego, CA 92121, USA.
Scott L
SL
Weinrich
Oncology Research Unit, Pfizer Global Research and Development, San Diego, CA 92121, USA.
Paul
P
Rejto
Oncology Research Unit, Pfizer Global Research and Development, San Diego, CA 92121, USA.
James G
JG
Christensen
Oncology Research Unit, Pfizer Global Research and Development, San Diego, CA 92121, USA.
Valeria R
VR
Fantin
Pfizer Biotherapeutics Clinical Research, Cambridge, MA 02140, USA.
Kenneth E
KE
Hung
Oncology Research Unit, Pfizer Global Research and Development, San Diego, CA 92121, USA. esmartin.phd@gmail.com petebelmont@gmail.com.
Eric S
ES
Martin
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002469:Cell Separation; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000737:chemistry*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D005434:Flow Cytometry; D011905:Genes, ras; D005818:Genetic Engineering; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D009368:Neoplasm Transplantation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics
D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins