Inhibition of PI3Kβ signaling with AZD8186 inhibits growth of PTEN-deficient breast and prostate tumors alone and in combination with docetaxel.
Loss of PTEN protein results in upregulation of the PI3K/AKT pathway, which appears dependent on the PI3Kβ isoform. Inhibitors of PI3Kβ have potential to reduce growth of tumors in which loss of PTEN drives tumor progression. We have developed a small-molecule inhibitor of PI3Kβ and PI3Kδ (AZD8186) and assessed its antitumor activity across a panel of cell lines. We have then explored the antitumor effects as single agent and in combination with docetaxel in triple-negative breast (TNBC) and prostate cancer models. In vitro, AZD8186 inhibited growth of a range of cell lines. Sensitivity was associated with inhibition of the AKT pathway. Cells sensitive to AZD8186 (GI50 < 1 μmol/L) are enriched for, but not exclusively associated with, PTEN deficiency. In vivo, AZD8186 inhibits PI3K pathway biomarkers in prostate and TNBC tumors. Scheduling treatment with AZD8186 shows antitumor activity required only intermittent exposure, and that increased tumor control is achieved when AZD8186 is used in combination with docetaxel. AZD8186 is a potent inhibitor of PI3Kβ with activity against PI3Kδ signaling, and has potential to reduce growth of tumors dependent on dysregulated PTEN for growth. Moreover, AZD8186 can be combined with docetaxel, a chemotherapy commonly used to treat advanced TBNC and prostate tumors. The ability to schedule AZD8186 and maintain efficacy offers opportunity to combine AZD8186 more effectively with other drugs.
Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Urs
U
Hancox
Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Sabina
S
Cosulich
Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Lyndsey
L
Hanson
Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Cath
C
Trigwell
Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Carol
C
Lenaghan
Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Rebecca
R
Ellston
Oncology iMED Gatehouse Park, Waltham, Massachusetts.
Hannah
H
Dry
Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Claire
C
Crafter
Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Bernard
B
Barlaam
Discovery Sciences AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Martina
M
Fitzek
Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Paul D
PD
Smith
Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Donald
D
Ogilvie
Oncology iMED Gatehouse Park, Waltham, Massachusetts.
Celina
C
D'Cruz
Oncology iMED Gatehouse Park, Waltham, Massachusetts.
Lillian
L
Castriotta
Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Stephen R
SR
Wedge
Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Lara
L
Ward
Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Steve
S
Powell
Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Mandy
M
Lawson
Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Barry R
BR
Davies
Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Elizabeth A
EA
Harrington
Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Emily
E
Foster
Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Marie
M
Cumberbatch
Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Stephen
S
Green
Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom. Simon.T.Barry@astrazeneca.com.
Simon T
ST
Barry
D000814:Aniline Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000008:administration & dosage* / Q000494:pharmacology; D000077143:Docetaxel; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000172:deficiency; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D043823:Taxoids / Q000008:administration & dosage*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C000595972:AZD8186; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D002867:Chromones; D000081082:Phosphoinositide-3 Kinase Inhibitors; D043823:Taxoids; D000077143:Docetaxel; D051059:PTEN Phosphohydrolase