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Review

AKT as a Therapeutic Target for Cancer

Mengqiu Song, Ann M. Bode, Zigang Dong and Mee-Hyun Lee
DOI: 10.1158/0008-5472.CAN-18-2738 Published March 2019

Abstract

Many cellular processes in cancer are attributed to kinase signaling networks. V-akt murine thymoma viral oncogene homolog (AKT) plays a major role in the PI3K/AKT signaling pathways. AKT is activated by PI3K or phosphoinositide-dependent kinases (PDK) as well as growth factors, inflammation, and DNA damage. Signal transduction occurs through downstream effectors such as mTOR, glycogen synthase kinase 3 beta (GSK3β), or forkhead box protein O1 (FOXO1). The abnormal overexpression or activation of AKT has been observed in many cancers, including ovarian, lung, and pancreatic cancers, and is associated with increased cancer cell proliferation and survival. Therefore, targeting AKT could provide an important approach for cancer prevention and therapy. In this review, we discuss the rationale for targeting AKT and also provide details regarding synthetic and natural AKT-targeting compounds and their associated studies.

Introduction

The AKT serine/threonine kinase, also known as protein kinase B (PKB), is an oncogenic protein that regulates cell survival, proliferation, growth, apoptosis, and glycogen metabolism (Fig. 1; ref. 1). AKT is activated by phosphorylation on Thr308 or Ser473 and it phosphorylates a variety of downstream protein substrates, including GSK3β, Bcl-2-associated death promoter, forkhead in rhabdomyosarcoma, and mouse double minute 2 homolog (2). Phosphorylated AKT (pAKT) has been implicated in the deregulation of apoptosis, proliferation, and cell motility because of its induction of signals that interfere with normal regulatory mechanisms activating mTOR (3, 4). Overexpression of pAKT is considered to be a therapeutic target for treating malignant tumors. For example, phosphorylation of AKT at Ser473 has been reported to promote breast cancer metastasis (5). At least one clinical study suggests that 20%–26% of patients with breast cancer expressing high levels of pAKT (Ser473) appear to be sensitive to treatment with paclitaxel or adjuvant doxorubicin plus cyclophosphamide and showed improved overall survival (OS) or disease-free survival (DFS; ref. 6). Therefore, the purpose of this review is to consider and analyze the role of AKT signaling in carcinogenesis and to examine progress in creating effective inhibitors of this kinase to treat various cancers.

Figure 1.
Figure 1.

Schematic diagram of the PI3K/AKT signaling pathway. Upstream target proteins of AKT are stimuli-induced receptor tyrosine kinases (RTK) and include PI3K, PDK, and mTOR complex 2 (mTORC2). Activated AKT phosphorylates downstream target proteins, including FOXO1, WEE1, GSK3β, and mTORC1, and the signaling results in cancer cell survival, cell-cycle effects, ribosome biogenesis, or protein synthesis. Activation of AKT can be inhibited by downregulation of upstream targets. Upstream target mediators include deguelin, sulforaphane, tehranolide, isoliquiritigenin, scutellarin, resveratrol, platycodin-D, or honokiol. Direct synthetic AKT inhibitors are MK-2206, AZD5363, GSK690693, GDC-0068, GSK2141795, GSK2110183, AT7867, CCT128930, BAY1125976, perifosine, AKT inhibitor VIII, and AKT1 and AKT-IN-1 and natural inhibitors, [6]-shogaol, herbacetin, and oridonin.

AKT as a Target in Cancer Therapy

AKT is overactivated in cancer

The overactivation of AKT is a common molecular characteristic of human malignancies (7, 8). Expression of certain oncogenes or loss of particular tumor suppressor genes can result in activation of the PI3K/AKT signaling pathway. For example, the amplification of Erb-B2 receptor tyrosine kinase 2 (ErbB2), mutations of EGFR/PI3K, or the loss of the tumor suppressor protein, PTEN, as well as mutations or amplification of AKT itself can result in increased AKT signaling in tumor cells (9). Mutated or deleted PTEN is common in many tumors and leads to overactivation of the PI3K/AKT network. Restoration of PTEN function enhances p21WAF1/CIP1-regulated cell-cycle inhibition by blocking PI3K/AKT signaling (10). Inhibition of NFκB-driven-COX-2 expression by cis-9,trans-11–conjugated linoleic acid contributed to antitumor effects by decreasing inhibitor of nuclear factor kappa kinase (IKK) activity and blocking PI3K/AKT signaling in TPA-treated hairless mouse skin in vivo (11). Ginsenoside Rg3 was also reported to attenuate NFκB signaling, possibly through the inactivation of AKT and ERKs and destabilization of mutant p53, leading to apoptosis of MDA-MB-231 breast cancer cells (12). Increased AKT1 activity has been observed in approximately 40% of breast and ovarian cancers and in over 50% of prostate cancers, and overactivation of AKT2 has been observed in about 30%–40% of ovarian and pancreatic cancers (13, 14). Increased AKT3 activity has been observed in estrogen receptor (ER)- or androgen receptor (AR)-deficient breast or prostate cancer cells, respectively, suggesting that AKT3 may contribute to the aggressiveness of hormone-independent cancers (15, 16). High expression levels of the phosphorylated AKT protein were observed in 75 of 83 (90.4%) cases of esophageal squamous cell carcinoma (ESCC) compared with normal esophageal mucosa (27.7% or 23/83 cases; ref. 17). This could affect the function of other cancer-associated proteins and lead to drug resistance. AKT-overexpressing cells displayed resistance to cisplatin, which was associated with overexpression of the antiapoptotic Bcl-xL protein that delayed the activation of the p53 signaling pathway (18, 19).

Overexpression or amplification of AKT1 and AKT2 is also associated with acquired resistance of ovarian cancer cells to paclitaxel (20). Constitutive pAKT (Ser473) expression under starvation conditions was exhibited by 13 of 19 lung cancer cell lines (21). The activation appeared to be due to increased upstream signaling. In an examination of lung cancer tissues, the percentage of AKT-positive samples in cancer and adjacent tissues was 76.47% (39/51) and 38.46% (5/13), respectively. Also, a significant correlation was observed between AKT expression and grade of cancer tissue differentiation (P < 0.05; ref. 22). In gastric cancer, cytoplasmic AKT expression was markedly increased in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutant tumors (23). The AKT rs1130233 polymorphism is associated with increased phosphorylated AKT expression in H. pylori-positive individuals. Also the polymorphism and H. pylori infection showed a significant interaction in the progression from normal tissue to atrophic gastritis and gastric cancers in human males (24). Phosphorylated AKT (Ser473) was also highly expressed in human papillomavirus (HPV) -related oropharyngeal squamous cell carcinoma in contrast to pAKT on Thr308. Notably, pAKT (Ser473) expression increased in primary tumors to progressive nodal disease (21.1%; P < 0.011; ref. 25).

pAKT as a prognostic marker in the clinic

The expression of pAKT is negatively correlated with survival in patients with ESCC (r = −0.473; P < 0.01) and the cumulative survival rate of pAKT-positive patients was significantly lower than that of pAKT-negative patients (P < 0.01; ref. 17). In patients with non–small cell lung cancer (NSCLC), pAKT (Ser473) levels were elevated in patients with acquired EGFR tyrosine kinase inhibitor (TKI) resistance (26). Moreover, the OS of pAKT-negative patients was 34.5 months, which is double the OS of 15.2 months of pAKT-positive patients (P = 0.0015). The progression-free survival (PFS) rates for patients undergoing EGFR-TKI treatment was 14.5 months for pAKT-negative patients compared with 6.1 months for pAKT-positive patients (P = 0.0037; ref. 26). These data revealed a potentially important role for increased pAKT levels as a novel biomarker for predicting a reduced initial EGFR-TKI response in patients (26). Activation of AKT also predicted the development of diffuse intrinsic pontine gliomas based on the loss of PTEN (27). Nuclear pAKT (Ser473) was predominantly overexpressed in 371 of 522 diffuse large B-cell lymphoma (DLBCL) cases. Compared with patients with low levels of pAKT, those with high expression had relatively poor PFS (P = 0.0027) and OS (P = 0.047). The 5-year PFS of patients with DLBCL with high expression of pAKT was 45.8% compared with 61% of patients with low expression (HR = 1.54; ref. 28).

Synopsis of Current AKT Inhibitors

Identifying AKT inhibitors that can block PI3K/AKT signaling by directly inhibiting AKT kinase activity or pAKT expression could attenuate cancer growth. Kinase inhibitors comprise three types (29). The first type competes with ATP and forms hydrogen bonds with the hinge region of the kinase, the second kind binds partially in the ATP-binding site and extends to the gatekeeping area and an adjacent allosteric site, and the third type functions as an allosteric inhibitor. Most AKT inhibitors in clinical development inhibit AKT 1, 2, and 3 and are referred to as pan-AKT inhibitors. Inhibitors comprise both synthetic and naturally occurring compounds (Fig. 1; Tables 1 and 2).

View this table:
Table 1.

The efficacy of inhibitors in animal experiments

View this table:
Table 2.

Clinical trials of AKT inhibitors

Synthetic compounds

GSK690693 (aminofurazan class) is an ATP-competitive pan-AKT kinase inhibitor [IC50, 2 nmol/L (AKT1), 13 nmol/L (AKT2), and 9 nmol/L (AKT3); ref. 9]. It suppresses the downstream AKT target, GSK3β, and reportedly inhibits the growth of BT-474 breast cancer cells in a xenograft mouse model (30). Clinical trials (NCT00493818, NCT00666081, phase I) testing GSK690693 have been cancelled or closed because the drug induced severe hyperglycemia (31).

GSK2141795 (uprosertib) is another ATP-competitive pan-AKT inhibitor. This drug was reported to enhance cisplatin-induced apoptosis in vitro and decrease phosphorylation of proline-rich AKT substrates in an SKOV3 ovarian cancer xenograft mouse model (32, 33). GSK2141795 was tested in a phase II clinical trial in combination with the MAPK/ERK1/2 inhibitor, trametinib, in patients with advanced melanoma (n = 48). The results showed that the combination had an acceptable toxicity profile, but unfortunately, patients expressing either the wild-type neuroblastoma RAS viral oncogene homolog (NRAS) or mutant NRAS (34) did not respond to the treatment.

GSK2110183 (afuresertib) is an orally available ATP-competitive and pan-AKT kinase inhibitor. It attenuated phosphorylation levels of various AKT substrates (e.g., GSK3β, PRAS40, FOXO, and caspase-9) in BT-474 breast cancer and LNCaP prostate cancer cell lines expressing ERBB2+, PIK3CA, K111N, or PTEN null (35). Dumble and colleagues reported that GSK2110183 showed a 65 and 21% effectiveness against hematological and solid tumor cells, respectively (35). An open-label, phase II single institution trial of a combination of intravenous infusion of ofatumumab and oral GSK2110183 in relapsed or refractory chronic lymphocytic leukemia patients (NCT01532700) was closed in June 2017. Results have been submitted to ClinicalTrials.gov, but are not yet publicly available.

AZD5363, another oral ATP-competitive pan-AKT inhibitor (IC50 < 10 nmol/L), showed a favorable pharmacokinetic and toxicity profile in a BT474c breast cancer xenograft mouse model (36). AZD5363 monotherapy suppressed proliferation of 41 of 182 solid/hematologic tumor cell lines with an IC50 < 3 μmol/L. Oral administration of AZD5363 resulted in the reduction of PRAS40, GSK3β, and S6 phosphorylation in a BT474c xenograft mouse model (37). Chronic oral treatment with AZD5363 inhibited growth of trastuzumab-resistant human epidermal growth factor receptor 2 (HER2+) breast cancer cells in a xenograft model. Furthermore, AZD5363 also significantly enhanced the anticancer activity of docetaxel, trastuzumab, or lapatinib in breast cancer xenograft mouse models (37). One clinical trial (NCT01353781) was conducted with AZD5363 in patients with solid tumors harboring an AKT mutation (AKT1E17K), including ER-positive/triple-negative breast, gynecologic, lung, prostate, and colorectal cancers. The median PFS among the patients with heavily pretreated AKT1E17K-mutant tumors was 5.5 months in patients with ER-positive breast cancer, 6.6 months in patients with gynecologic cancer, and 4.2 months in patients with other solid tumors. These results suggest that AZD5363 might be effective against tumors harboring the AKT1E17K mutation (38).

GDC-0068 (ipatasertib) is an ATP-competitive pan-AKT inhibitor exerting antiproliferative and antisurvival effects against several cancer cell lines by inhibiting the PI3-K/AKT pathway (39). Inhibition of AKT activity by this compound blocked cell-cycle progression and reduced viability of cancer cell lines, including PC-3 (PTEN deletion) prostate cancer cells, BT474M1 (PIK3CAK111N mutant and HER2-amplified) breast cancer cells, and IGROV-1 (PTENT319fsX1/Y155C and PIK3CA*1069W) ovarian cancer cells (40). GDC-0068 inhibited AKT signaling, not only in cultured human cancer cell lines (PC-3, BT474M1, IGROV-1), but oral administration decreased ovarian, prostate, breast, glioblastoma, colorectal, NSCLC, and melanoma xenograft cell growth in which AKT expression was elevated (40). GDC-0068 also effectively inhibited growth in vivo in tumors expressing AKT activated by genetic alterations, including PTEN loss, PIK3CA mutations/amplifications, or HER2 overexpression (40). Furthermore, a combination of GDC-0068 and docetaxel or carboplatin attenuated xenograft growth of PC-3 (prostate), MCF7-neo/HER2 (breast), OVCAR3 (ovarian) cancer cells in mice. A first-in-man phase I study of ipatasertib (NCT01090960) demonstrated robust and safe targeting of AKT in patients with solid tumors and indicated that this drug was well tolerated and inhibited PRAS40, GSK3β, and mTOR in paired on-treatment biopsies (41). Ipatasertib is now being further evaluated in phase II studies.

AT7867 is an ATP-competitive inhibitor of AKT1/2/3 and ribosomal protein S6 kinase beta-1 (p70S6K)/protein kinase A (PKA) that exhibits little activity outside the protein kinase A, G, and C (AGC) kinase family. AT7867 significantly inhibited the growth of PTEN-null U87MG human glioblastoma cell xenografts and its bioavailability in mice was 44% when administered orally (42).

CCT128930 is an ATP-competitive and selective AKT2 inhibitor (IC50 = 6 nmol/L) and has a 28-fold selectivity for AKT2 compared with the closely related PKA kinase. CCT128930 exhibited antitumor activity against PTEN-null U87MG glioblastoma and HER2-positive, PIK3CA-mutant BT474 breast cancer xenografts in mice (43). Neither AT7867 nor CCT128930 has been enrolled in clinical trials at this time.

MK-2206 is an orally available allosteric AKT1/2 inhibitor and exhibits IC50 values of 8, 12, and 65 nmol/L against AKT1, 2, and 3, respectively (44). Allosteric AKT inhibitors do not result in hyperphosphorylation of AKT at Ser473/Thr308, unlike ATP-competitive inhibitors (45). MK-2206 exhibited potent antiproliferative activity against various cancer cell types harboring PI3KCA mutations, PTEN loss, upstream RTK gene amplification or overactivation, and mutation of AKT itself. A dose-escalation clinical trial investigated tolerability, safety, and MTD of MK-2206 in 33 patients with advanced solid tumors and in 72 patients previously treated with carboplatin/paclitaxel, docetaxel, or erlotinib (NCT00848718; refs. 46, 47). A phase II trial (NCT01333475) investigated the combination of MK-2206 with selumetinib, a MAPK kinase 1/2 (MEK1/2, MAP2K1/2) inhibitor (48). Unfortunately, no objective responses were observed. However, determining whether the lack of response was due to a suboptimal dose and schedule or to an AKT/MEK-independent activation of ERKs was difficult. A recent clinical trial (NCT01369849) examined the efficacy of combining MK-2206 with bendamustine and rituximab in relapsed or refractory chronic lymphocytic leukemia. The overall response rate was a promising 92% and the median PFS and treatment-free survival was 16 and 24 months, respectively. These results indicate that AKT inhibition combined with chemo-immunotherapy might be a promising treatment option (49).

BAY 1125976 is another AKT1/2 inhibitor that binds into an allosteric binding pocket formed by the kinase and PH domains of AKT1 or AKT2 (50). BAY 1125976 was well-tolerated in vivo and demonstrated dose-dependent antitumor efficacy in multiple tumor models with an activated PI3K/AKT/mTOR pathway, including AKT (E17K) mutant- or PTEN loss–driven tumors (50). BAY 1125976 effectively blocked AKT signaling by inhibiting pAKT and its downstream target, eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), in AKT-mediated tumorigenesis (51). A phase I dose escalation study (NCT01915576) for “all comer” patients was completed in 2016.

“AKT1 and AKT2-IN-1” is an allosteric inhibitor of AKT1 (IC50, 3.5 nmol/L) and AKT2 (IC50, 42 nmol/L). AKT1 and AKT2-IN-1 is dependent on the PH-domain for AKT inhibition and is selective for AKT1/2 rather than AKT3 (IC50 = 1.9 μmol/L), or other members of the AGC kinase family (>50 μmol/L). AKT1 and AKT2-IN-1 was well tolerated in mice and attenuated levels of AKT in blood samples. AKT1 and AKT2-IN-1 treatment in an A2780 ovarian carcinoma cell xenograft model showed 80% and 75% inhibition of AKT1 and AKT2, respectively (52).

Perifosine is an oral alkyl-phospholipid AKT inhibitor that blocks the translocation of AKT to the plasma membrane and its subsequent phosphorylation, thereby exerting a marked cytotoxic effect against human tumor cell lines (53). An in vivo study showed that perifosine combined with temozolomide was more effective than temozolomide treatment alone against platelet-derived growth factor B-driven gliomas in mice (53). Patel and colleagues reported that perifosine (20 μmol/L) induced cell-cycle arrest at both the G1 and G2–M phases and increased p21WAF1 expression in both tumor suppressor p53 wild-type and knockout cells (54). In contrast, perifosine had no effect on cyclin-dependent kinase inhibitor 1A (p21WAF1) or cell cycle in p21-knockout variants expressed in head and neck squamous carcinoma cells. In addition, perifosine markedly decreased the level of pAKT beginning at 10 minutes and lasting up to 24 hours and moderately decreased the level of pS6 from 1 to 24 hours in rats (55). This compound was demonstrated to have manageable or no toxicity from 25 to 125 mg/m2/day in a phase I clinical study (NCT00776867) in recurrent/refractory pediatric central nervous system and solid tumor patients (56). Perifosine combined with sorafenib showed promising activity against Hodgkin lymphoma in a phase I clinical study (NCT00019656; ref. 57). This compound was also examined as a second- or third-line therapy in combination with capecitabine in patients with metastatic colorectal cancer (NCT00398879; ref. 58). Additional phase I and phase I/Ib clinical studies confirmed that perifosine monotherapy was a safe and well-tolerated treatment in children with high-risk neuroblastoma (HR-NB; ref. 59). The combination of perifosine and an mTOR inhibitor (temsirolimus) was found to be safe and reasonable at a dose level of 25–75 mg/m2/day orally and 25–75 mg/m2 i.v. weekly, respectively, in patients with recurrent/refractory pediatric solid tumors (NCT01049841, NCT00776867; refs. 59, 60). Although perifosine has been studied in many trials, it has not been found to be superior to other first- or second-line cancer therapies. In 2012, Cho and colleagues (61) demonstrated that perifosine was well-tolerated and showed activity in patients with advanced renal cell carcinoma (RCC) after failure on VEGF-targeted therapy. However, its activity was not superior to currently available second-line agents (NCT00448721). Apart from this, a phase II trial (2007) of perifosine (NCT00058214) in patients with biochemically recurrent, hormone-sensitive prostate cancer also showed that the response to perifosine as a single agent did not pass prespecified prostate-specific antigen (PSA) criteria. However, 20% of patients showed PSA reduction in the NCT00058214 study (62), suggesting that perifosin might have modest single-agent clinical activity. Overall, perifosine was shown in several clinical trials to have significant activity either as a single agent or in combination therapy. However, more mechanistic research is needed for its development into an effective therapeutic agent.

The AKT inhibitor, VIII, was developed based on 2, 3-diphenylquinoxaline, which was discovered through a high-throughput screening effort to identify compounds capable of inhibiting all 3 AKT isoforms (63, 64). As reported, many tumor cell lines, including HT29 (colon), MCF7 (breast), A2780 (ovarian), and LNCaP (prostate), are highly sensitive to VIII (63). This inhibitor effectively decreased cell proliferation and increased apoptosis by translocation of phosphatidylserine (PS), induction of cleaved caspase-9, caspase-3, and PARP (65).

Natural compounds

Because the structure of AKT has been solved, its many functions have been gradually revealed. Many pharmaceutical companies and academic laboratories are actively developing natural compounds that directly target AKTs. Numerous preclinical investigations have shown that some herbs and natural phytochemicals can inhibit AKT activity directly (Fig. 1).

[6]-Shogaol from ginger root inhibited the PI3K/AKT/mTOR signaling pathway by directly targeting AKT1 and AKT2, but not PI3K or mTOR. Its inhibitory activity occurred through its binding to an allosteric site of AKT at the lower interface between the N- and C-lobes of the kinase domain. This compound suppressed proliferation of NSCLC, hepatocarcinoma, skin, and ovarian cancer cells (66–69). Another compound, oridonin (rabdosia rubescens), decreased cell proliferation in vitro and patient-derived xenograft growth in vivo by directly targeting AKT competitive with ATP (70). Herbacetin found in flaxseed directly inhibits the kinase activities of AKT1/2 and ornithine decarboxylase (ODC), but not MEKs or ERKs. This resulted in suppressed tumor growth in DMBA/TPA or solar UV-induced skin carcinogenesis and melanoma in in vitro and in vivo models (71, 72). Deguelin (Mondulea Sericea) attenuated tobacco-induced lung tumorigenesis and premalignant human bronchial epithelial cell growth by downregulating the PI3K/AKT signaling pathway (73, 74). Sulforaphane (SFN) from cruciferous vegetables induces G2–M phase arrest and apoptosis of osteosarcoma cells and, combined with 2 Gy of radiation, induced apoptosis by suppressing AKT and ERKs expression (75–77). SFN reportedly inhibits tumor cell growth because the electrophilic carbon in the isothiocyanate moiety reacts with the nucleophilic group on amino acids and covalently modifies them, thus decreasing kinase activity of PI3K, AKT, and NF-κB (78). Tehranolide (Artemisia diffusa) decreased growth in MCF-7 breast cancer cell xenografts in mice through the production of reactive oxygen species (ROS) and downregulation of pAKT (79). Isoliquiritigenin (ISL) from licorice root possesses anticancer activities such as inhibition of proliferation and angiogenesis, induction of cell-cycle arrest and apoptosis, and obstruction of metastasis (80, 81). ISL suppressed growth and induced apoptosis both in MCF-7 and MDA-MB-231 breast cancer cells and repressed the arachidonic acid metabolic network and inactivated the AKT pathway in vivo (82). ISL increases PTEN expression by decreasing miR-374a expression, thereby inhibiting AKT signaling in breast cancer therapies (82–84). Scutellarin is an active flavonoid from Erigeron breviscapine and blocked the migration and invasion of HepG2 cells by inhibiting the STAT3/girdin/AKT axis (85). Resveratrol (RES) is found in grapes, berries, and peanuts and inhibited activation of multiple survival pathways, including the PI3K/AKT pathway, thereby inducing cancer cell apoptosis (86, 87). RES reportedly inhibited proliferation and migration of hepatocellular carcinoma and colon cancer cells through the downregulation of the PI3K/AKT pathway by modifying sirtuin 1-mediated posttranslational modification and elevating bone morphogenetic protein 7 (88, 89). RES induced apoptosis by specifically targeting pAKT and mediators of apoptosis in H460 lung cancer cells (90). It also influenced autophagic/apoptotic death in drug-resistant oral cancer cells mediated through adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) and AKT/mTOR signaling (91). RES was able to induce cell-cycle arrest in human gastric cancer MGC803 cells by regulating the expression of the PTEN/PI3K/AKT signaling pathway (92). Platycodin-D (PD) from Platycodon grandiflorum root induced autophagy of NSCLC cells by inhibiting PI3K/AKT/mTOR signaling and activating the c-Jun N-terminal kinases (JNKs)/p38 MAPK signaling pathways (93). The combination of PD and the synthetic AKT inhibitor MK-2206 attenuated the feedback activation of the AKT pathway and led to blockade of AKT/4E-BP1 function, thereby inhibiting proliferation and inducing apoptosis of NSCLC (94). Honokiol (Magnolia officinalis) induced autophagic cell death by downregulating PI3K/AKT/mTOR signaling in U87MG human glioma or mouse neuroblastoma cells (95, 96).

Although clinical trials have not yet been conducted with any natural compounds targeting AKT kinase activity, patients are either enrolled or are being enrolled in clinical trials focusing on colon cancer prevention (NCT00256334) or in postmenopausal women with high body mass index (NCT01370889) to test RES and grape powder extract, respectively. Other trials include ginger extract in colon cancer prevention (NCT01344538; ref. 97) and sulforaphane in recurrent prostate cancer (NCT01228084). In the NCT00256334 study, the most significant results were observed in subjects treated with grape powder (80 g per day; GP80). GP80 decreased cyclin D and axinII gene expression, which are Wnt (wingless-type murine-mammary-tumor virus integration site) target genes in colon cancer (98). Treatment with RES (1 g/day) decreased the risk of breast cancer in postmenopausal women with high BMI by increasing both urinary 2-hydroxyestrone (73%) and sex hormone-binding globulin (10%) (99). However, researchers and clinicians are still trying to identify proper biomarkers and optimize doses of natural compounds as chemopreventive or therapeutic agents for use in the clinic.

Perspective and Conclusions

For many years, AKT has been considered as an attractive target for cancer therapy and prevention. AKT inhibitors have taken a large step forward through the development of synthetic and natural compounds that directly target AKT or AKT-related signaling pathways. Thus far, only a few AKT inhibitors have been approved by the FDA for cancer treatment. Miltefosine (Impavido, phospholipid drug) originally was used against cutaneous or mucosal leishmaniasis (100). As an AKT inhibitor, miltefosine affects human immunodeficiency virus-1 (HIV-1)-infected macrophages (101) and patients are being enrolled in a clinical trial to test its effectiveness as a cancer therapeutic (NCT02366884). Because PI3K is an upstream kinase of AKT, either inhibitors of PI3K or mTOR could affect the AKT signaling cascades. The FDA-approved PI3K or mTOR inhibitors include idelalisib (a PI3K delta inhibitor) used in patients with leukemia and lymphoma; copanlisib (a PI3K alpha/delta inhibitor) to treat adult patients with relapsed follicular lymphoma; and sirolimus (an mTOR inhibitor) to treat patients with lymphangioleiomyomatosis with gene mutations of the tuberous sclerosis complex 2 gene in renal cell carcinoma (RCC); and everolimus (an mTOR inhibitor) to treat RCC, pancreatic, and breast cancers.

Targeting AKT has therapeutic potential but also has pitfalls because of the complex signaling pathway network. MK-2206 treatment downregulated the expression level of p-AKT (both Ser473 and Thr308) in DLBCL cells but its upstream proteins, including PI3K, mTORC2, and p-FAK, were overactivated to compensate (28). The evaluation of DLBCL patient samples also indicated that Myc and Bcl-2 were also overexpressed along with upregulation of phosphorylated AKT (28). To avoid the phenomenon of compensatory resistance, AKT-specific inhibitors could be used in combination with PI3K or mTOR inhibitors or dual or triple inhibition of those targets to reach better pharmacokinetic properties. NVP-BEZ235 is well-known as a dual inhibitor of PI3K and mTOR, and synergistically with cisplatin inhibits tumor growth in FaDu hypopharyngeal squamous cell carcinoma (102). This compound is also synergistically effective with sunitinib against prostate cancer (103) and with temozolomide against glioblastoma multiforme (104). However, this compound causes dephosphorylation of AKT (Thr308) for only a short time and hyperphosphorylation occurs again with continuous exposure. INK128, an mTOR inhibitor, also caused dephosphorylation of S6K1 and AKT (Ser 473) for 1 hour, but AKT was again phosphorylated at both Ser and Thr residues again by 24 hours. Interestingly, the PDK1 inhibitor, GSK233470, also could not overcome the reoccurring phosphorylation successfully (105). Predictably, the combination of PI3-K/mTOR (NVP-BEZ235) and an AKT inhibitor (MK-2206) suppressed the hyperphosphorylation of AKT at 24 hours and also showed synergistically decreased cell viability with the combination index (CI) ranging from 0.08 to 0.87 (105). In line with the in vitro work, a combination of NVP-BEZ235 and MK-2206 treatment also resulted in an additional 46% reduction in tumor weight compared with single treatment with NVP-BEZ235 (105). Thus, this brings an entirely new perspective in the triple-targeting of PI3K/AKT/mTOR signaling in cancer therapy.

Multivariate survival analysis also revealed that Myc or Bcl-2 elevation and TP53 mutation status could contribute to patient survival time, thus making the overexpression of phosphorylated AKT an insignificant independent prognostic marker in DLBCL OS (28). Moreover, PIK3CA mutation and PTEN loss might affect AKT signaling and the PIK3CA-mutant cells such as MCF-7, HCT-116, HCT-15, and SW-948 showed strongly diminished AKT signaling. Furthermore, PIK3CA-mutant cells with low levels of phosphorylated AKT expression exhibited less dependence on AKT signaling although PIK3CA was still essential for tumorigenesis (106).

Mutation of AKT in exon 20 has been reported to be 100% in gastric cancer. In addition, mutation levels of 56% frequently occur in exon 9 and 40% in exon 1. But until now, these mutations have not been reported to be statistically significant (107). An E17K mutation in the AKT1 pleckstrin homology domain (PH domain) has been identified in human colorectal, breast, and ovarian cancers functioning to activate AKT1 and its downstream signaling and subsequently stimulating tumorigenesis (108). Overall, AKT signaling might be influenced by upregulation of PI3K or mTOR in compensation for or mutation of upstream signaling. Multiple targeting of the entire AKT signaling pathway or combination therapy will be novel strategies for future cancer therapies. Therefore, AKT is a potential therapeutic focus of cancer and should continue to gain more and more attention as a target for the development of a variety of AKT inhibitors for cancer prevention and treatment.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

This work was supported by grants from the NIH (CA187027, CA166011, CA196639), Key Program of Henan Province, China (grant no. 161100510300 to Z. Dong), the National Natural Science Foundation of China (NSFC81672767 to M.-H. Lee), and Henan Provincial Government, China.

  • Received August 31, 2018.
  • Revision received November 15, 2018.
  • Accepted December 26, 2018.
  • Published first February 26, 2019.

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AKT as a Therapeutic Target for Cancer
Mengqiu Song, Ann M. Bode, Zigang Dong and Mee-Hyun Lee
Cancer Res March 15 2019 (79) (6) 1019-1031; DOI: 10.1158/0008-5472.CAN-18-2738
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