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Target Overview
The cell signaling network, which includes phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR), is frequently dysregulated in human cancer. AKT is a central node in this network, modulating a range of substrates involved in growth, apoptosis, and metabolism. There are 3 isoforms of AKT: AKT1, 2, and 3. The most commonly mutated genes that result in activation of the PI3K/AKT/PTEN pathway are activating mutations of PIK3CA, AKT1 and loss-of-function alterations of PTEN.1,2
AKT activation has been shown to mediate resistance to inhibitors of receptor tyrosine kinases, antihormonal agents, and chemotherapy.3
Compound Overview
Capivasertib,a a pan-AKT kinase inhibitor (against isoforms AKT1, AKT2, and AKT3), inhibits AKT activity, leading to dephosphorylation of downstream targets. Given the critical position of AKT in this pathway, capivasertib’s mechanism of action serves to restrict the flow of upstream signaling, including that from activating mutations in PIK3CA and loss-of-function PTEN alterations, as well as activating mutations in AKT1 itself, before those can have further downstream effects in driving tumor growth.4-7
aFormerly known as AZD5363, discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited.
Mechanism of Action
Reference: Martini M, De Santis MC, Braccini L, et al. Ann Med. 2014;46(6):372-383.
This mechanism of action is depicted for breast cancer cells and is applicable to prostate cancer, where the androgen receptor (AR) plays a role in the nucleus, analogous to the estrogen receptor (ER) in the breast cancer setting. AR pathway blockade with ARPI therapy is the standard-of-care, but inhibiting the AR pathway can result in upregulation of the AKT pathway.8-10
References
1. Altomare DA, Testa JR. Oncogene. 2005;24(50):7455-7464. 2. Liu P, Cheng H, Roberts TM, et al. Nat Rev Drug Discov. 2009;8(8):627-644. 3. Clark AS, West K, Streicher S, et al. Mol Cancer Ther. 2002;1(9):707-717. 4. Davies BR, Greenwood H, Dudley P, et al. Mol Cancer Ther. 2012;11(4):873-887. 5. Miller TW, Rexer BN, Garrett JT, et al. Breast Cancer Res. 2011;13(6):224 6. Miller C, Sommavilla R, Murphy D, et al. Br J Clin Pharmacol 2023;89(11):3330-3339 7. Miricescu D, Totan A, Stanescu-Spinu II, et al. Int J Mol Sci 2020;22(1):173 8. Gasmi A, Roubaud G, Dariane C, et al. J Clin Med. 2021;11:160. 9. Mulholland DJ, Tran LM, Li Y, et al. Cancer Cell. 2011;19:792–804. 10. Carver BS, Chapinski C, Wongvipat J, et al. Cancer Cell. 2011;19:575–586.
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Abbreviations
AI
aromatase inhibitor
AKT
protein kinase B/also known as PKB
AR
androgen receptor
BC
breast cancer
BID
twice daily
CBR
clinical benefit rate
CDK4/6
cyclin-dependent kinase 4/6
CDK4/6i
cyclin-dependent kinase 4/6 inhibitor
DoR
duration of response
ET
endocrine therapy
HER2
human epidermal growth factor receptor 2
HR
hormone receptor
HRQoL
health-related quality of life
mTOR
mechanistic or mammalian target of rapamycin
mTPI-2
modified toxicity probability interval
ORR
overall or objective response rate
OS
overall survival
PFS
progression-free survival
PFS2
time to second progression or death
PI3K
phosphoinositide 3-kinase
PIK3CA
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha
PO
per oral
PTEN
phosphatase and tensin homolog
R
randomization
rPFS
radiographic progression-free survival
RTK
receptor tyrosine kinase
SERD
selective estrogen receptor degrader
Target Overview
The cell signaling network, which includes phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR), is frequently dysregulated in human cancer. AKT is a central node in this network, modulating a range of substrates involved in growth, apoptosis, and metabolism. There are 3 isoforms of AKT: AKT1, 2, and 3. The most commonly mutated genes that result in activation of the PI3K/AKT/PTEN pathway are activating mutations of PIK3CA, AKT1 and loss-of-function alterations of PTEN.1,2
AKT activation has been shown to mediate resistance to inhibitors of receptor tyrosine kinases, antihormonal agents, and chemotherapy.3
Compound Overview
Capivasertib,a a pan-AKT kinase inhibitor (against isoforms AKT1, AKT2, and AKT3), inhibits AKT activity, leading to dephosphorylation of downstream targets. Given the critical position of AKT in this pathway, capivasertib’s mechanism of action serves to restrict the flow of upstream signaling, including that from activating mutations in PIK3CA and loss-of-function PTEN alterations, as well as activating mutations in AKT1 itself, before those can have further downstream effects in driving tumor growth.4-7
aFormerly known as AZD5363, discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited.
Mechanism of Action
Reference: Martini M, De Santis MC, Braccini L, et al. Ann Med. 2014;46(6):372-383.
This mechanism of action is depicted for breast cancer cells and is applicable to prostate cancer, where the androgen receptor (AR) plays a role in the nucleus, analogous to the estrogen receptor (ER) in the breast cancer setting. AR pathway blockade with ARPI therapy is the standard-of-care, but inhibiting the AR pathway can result in upregulation of the AKT pathway.8-10
References
1. Altomare DA, Testa JR. Oncogene. 2005;24(50):7455-7464. 2. Liu P, Cheng H, Roberts TM, et al. Nat Rev Drug Discov. 2009;8(8):627-644. 3. Clark AS, West K, Streicher S, et al. Mol Cancer Ther. 2002;1(9):707-717. 4. Davies BR, Greenwood H, Dudley P, et al. Mol Cancer Ther. 2012;11(4):873-887. 5. Miller TW, Rexer BN, Garrett JT, et al. Breast Cancer Res. 2011;13(6):224 6. Miller C, Sommavilla R, Murphy D, et al. Br J Clin Pharmacol 2023;89(11):3330-3339 7. Miricescu D, Totan A, Stanescu-Spinu II, et al. Int J Mol Sci 2020;22(1):173 8. Gasmi A, Roubaud G, Dariane C, et al. J Clin Med. 2021;11:160. 9. Mulholland DJ, Tran LM, Li Y, et al. Cancer Cell. 2011;19:792–804. 10. Carver BS, Chapinski C, Wongvipat J, et al. Cancer Cell. 2011;19:575–586.
Clinical trial information
Select trial for more information
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Abbreviations
AI
aromatase inhibitor
AKT
protein kinase B/also known as PKB
AR
androgen receptor
BC
breast cancer
BID
twice daily
CBR
clinical benefit rate
CDK4/6
cyclin-dependent kinase 4/6
CDK4/6i
cyclin-dependent kinase 4/6 inhibitor
DoR
duration of response
ET
endocrine therapy
HER2
human epidermal growth factor receptor 2
HR
hormone receptor
HRQoL
health-related quality of life
mTOR
mechanistic or mammalian target of rapamycin
mTPI-2
modified toxicity probability interval
ORR
overall or objective response rate
OS
overall survival
PFS
progression-free survival
PFS2
time to second progression or death
PI3K
phosphoinositide 3-kinase
PIK3CA
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha
PO
per oral
PTEN
phosphatase and tensin homolog
R
randomization
rPFS
radiographic progression-free survival
RTK
receptor tyrosine kinase
SERD
selective estrogen receptor degrader