Cabozantinib Inhibits Abiraterone's Upregulation of IGFIR Phosphorylation and Enhances Its Anti-Prostate Cancer Activity.
OBJECTIVE
Abiraterone improves the overall survival of men with metastatic castration-resistant prostate cancer. However, de novo or adaptive resistance to abiraterone limits its activity. Rational combinations of drugs with different mechanisms of action that overcome resistance mechanisms may improve the efficacy of therapy. To that end, we studied the molecular and phenotypic effects of the combination of cabozantinib plus abiraterone.


METHODS
Three prostate cancer cell lines were used to interrogate the in vitro molecular and antiproliferative effects of the single agents and combination of cabozantinib and abiraterone. The in vivo impact of the combination was assessed using the LAPC4-CR xenograft mouse model.


RESULTS
In vitro proliferation studies demonstrated single-agent doses between 2 μmol/L and 10 μmol/L for abiraterone and cabozantinib inhibit prostate cancer cell proliferation in a dose-dependent manner, and the anticancer activity of abiraterone is enhanced when combined with cabozantinib. In vivo LAPC4-CR xenograft mouse studies also showed that cabozantinib can improve the antitumor activity of abiraterone. Cabozantinib, a multiple receptor tyrosine kinase inhibitor, enhances the ability of abiraterone to inhibit AR activity in a cell line-dependent manner. In addition, our cell line studies demonstrate abiraterone-stimulated insulin-like growth factor I receptor (IGFIR) phosphorylation with downstream activation of MEK1/2 and ERK1/2, and that this potential adaptive resistance mechanism was inhibited by cabozantinib.


CONCLUSIONS
Cabozantinib can enhance the efficacy of abiraterone by blocking multiple compensatory survival mechanisms, including IGFIR activation, and supports the assessment of the combination in a clinical trial.
Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Xiaodong
X
Wang
Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Ying
Y
Huang
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Amanda
A
Christie
Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Michaela
M
Bowden
Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Gwo-Shu Mary
GS
Lee
Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Christopher_Sweeney@dfci.harvard.edu Philip_Kantoff@dfci.harvard.edu.
Philip W
PW
Kantoff
Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Christopher_Sweeney@dfci.harvard.edu Philip_Kantoff@dfci.harvard.edu.
Christopher J
CJ
Sweeney
D000736:Androstenes / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004336:Drug Antagonism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D051379:Mice; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000736:Androstenes; D000813:Anilides; D000970:Antineoplastic Agents; D011725:Pyridines; D011944:Receptors, Androgen; C558660:cabozantinib; D020794:Receptor Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; C089740:abiraterone