Tumors with AKT1E17K Mutations Are Rational Targets for Single Agent or Combination Therapy with AKT Inhibitors.
AKT1(E17K) mutations occur at low frequency in a variety of solid tumors, including those of the breast and urinary bladder. Although this mutation has been shown to transform rodent cells in culture, it was found to be less oncogenic than PIK3CA mutations in breast epithelial cells. Moreover, the therapeutic potential of AKT inhibitors in human tumors with an endogenous AKT1(E17K) mutation is not known. Expression of exogenous copies of AKT1(E17K) in MCF10A breast epithelial cells increased phosphorylation of AKT and its substrates, induced colony formation in soft agar, and formation of lesions in the mammary fat pad of immunodeficient mice. These effects were inhibited by the allosteric and catalytic AKT inhibitors MK-2206 and AZD5363, respectively. Both AKT inhibitors caused highly significant growth inhibition of breast cancer explant models with AKT1(E17K) mutation. Furthermore, in a phase I clinical study, the catalytic Akt inhibitor AZD5363 induced partial responses in patients with breast and ovarian cancer with tumors containing AKT1(E17K) mutations. In MGH-U3 bladder cancer xenografts, which contain both AKT1(E17K) and FGFR3(Y373C) mutations, AZD5363 monotherapy did not significantly reduce tumor growth, but tumor regression was observed in combination with the FGFR inhibitor AZD4547. The data show that tumors with AKT1(E17K) mutations are rational therapeutic targets for AKT inhibitors, although combinations with other targeted agents may be required where activating oncogenic mutations of other proteins are present in the same tumor.
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, United Kingdom. barry.davies@astrazeneca.com.
Barry R
BR
Davies
Gatehouse Park, Waltham, Massachusetts.
Nin
N
Guan
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
Armelle
A
Logie
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
Claire
C
Crafter
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
Lyndsey
L
Hanson
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
Vivien
V
Jacobs
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
Neil
N
James
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
Philippa
P
Dudley
Gatehouse Park, Waltham, Massachusetts.
Kelly
K
Jacques
Gatehouse Park, Waltham, Massachusetts.
Brendon
B
Ladd
Gatehouse Park, Waltham, Massachusetts.
Celina M
CM
D'Cruz
Gatehouse Park, Waltham, Massachusetts.
Michael
M
Zinda
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
Justin
J
Lindemann
Department of Breast and Medical Oncology, National Cancer Centre Hospital, Tokyo, Japan.
Makoto
M
Kodaira
Department of Breast and Medical Oncology, National Cancer Centre Hospital, Tokyo, Japan.
Kenji
K
Tamura
Gatehouse Park, Waltham, Massachusetts.
Emma L
EL
Jenkins
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D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D011743:Pyrimidines; D011758:Pyrroles; D051057:Proto-Oncogene Proteins c-akt; D004318:Doxycycline; C575618:capivasertib