Targeting the phosphoinositide-3 (PI3) kinase pathway in breast cancer

The phosphoinositide-3 kinase (PI3K) pathway has been identified as an important target in breast cancer research for a number of years, but is new to most clinicians responsible for the daily challenges of breast cancer management. In fact, the PI3K pathway is probably one of the most important pathways in cancer metabolism and growth. Mutations in the PI3K pathway are frequent in breast cancer, causing resistance to human epidermal growth factor receptor 2-targeted agents and, possibly, to hormonal agents as well. Available agents that affect the PI3K pathway include monoclonal antibodies and tyrosine kinase inhibitors, as well as PI3K inhibitors, Akt inhibitors, rapamycin analogs, and mammalian target of rapamycin (mTOR) catalytic inhibitors. Multiple PI3K inhibitors are currently under development, including pure PI3K inhibitors, compounds that block both PI3K and mTOR (dual inhibitors), pure catalytic mTOR inhibitors, and inhibitors that block Akt. It is likely that these agents will have to be given in combination with other signal inhibitors because anti-mTOR agents and PI3K inhibitors may result in the activation of compensatory feedback loops that would in turn result in decreased efficacy. This article reviews current data related to the PI3K pathway, its role in breast cancer, the frequency with which PI3K is aberrant in breast cancer, and the potential clinical implications of using agents that target the PI3K pathway.     

Metabolic biomarkers for response to PI3K inhibition in basal-like breast cancer

Introduction

The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in cancer cells through numerous mutations and epigenetic changes. The recent development of inhibitors targeting different components of the PI3K pathway may represent a valuable treatment alternative. However, predicting efficacy of these drugs is challenging, and methods for therapy monitoring are needed. Basal-like breast cancer (BLBC) is an aggressive breast cancer subtype, frequently associated with PI3K pathway activation. The objectives of this study were to quantify the PI3K pathway activity in tissue sections from xenografts representing basal-like and luminal-like breast cancer before and immediately after treatment with PI3K inhibitors, and to identify metabolic biomarkers for treatment response.

Methods

Tumor-bearing animals (n = 8 per treatment group) received MK-2206 (120 mg/kg/day) or BEZ235 (50 mg/kg/day) for 3 days. Activity in the PI3K/Akt/mammalian target of rapamycin pathway in xenografts and human biopsies was evaluated using a novel method for semiquantitative assessment of Akt^ser473 phosphorylation. Metabolic changes were assessed by ex vivo high-resolution magic angle spinning magnetic resonance spectroscopy.

Results

Using a novel dual near-infrared immunofluorescent imaging method, basal-like xenografts had a 4.5-fold higher baseline level of pAkt^ser473 than luminal-like xenografts. Following treatment, basal-like xenografts demonstrated reduced levels of pAkt^ser473 and decreased proliferation. This correlated with metabolic changes, as both MK-2206 and BEZ235 reduced lactate concentration and increased phosphocholine concentration in the basal-like tumors. BEZ235 also caused increased glucose and glycerophosphocholine concentrations. No response to treatment or change in metabolic profile was seen in luminal-like xenografts. Analyzing tumor sections from five patients with BLBC demonstrated that two of these patients had an elevated pAkt^ser473 level.

Conclusion

The activity of the PI3K pathway can be determined in tissue sections by quantitative imaging using an antibody towards pAkt^ser473. Long-term treatment with MK-2206 or BEZ235 resulted in significant growth inhibition in basal-like, but not luminal-like, xenografts. This indicates that PI3K inhibitors may have selective efficacy in basal-like breast cancer with increased PI3K signaling, and identifies lactate, phosphocholine and glycerophosphocholine as potential metabolic biomarkers for early therapy monitoring. In human biopsies, variable pAkt^ser473 levels were observed, suggesting heterogeneous PI3K signaling activity in BLBC.     

PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer

There is a strong rationale to therapeutically target the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway in breast cancer since it is highly deregulated in this disease and it also mediates resistance to anti-HER2 therapies. However, initial studies with rapalogs, allosteric inhibitors of mTORC1, have resulted in limited clinical efficacy probably due to the release of a negative regulatory feedback loop that triggers AKT and ERK signaling. Since activation of AKT occurs via PI3K, we decided to explore whether PI3K inhibitors prevent the activation of these compensatory pathways. Using HER2-overexpressing breast cancer cells as a model, we observed that PI3K inhibitors abolished AKT activation. However, PI3K inhibition resulted in a compensatory activation of the ERK signaling pathway. This enhanced ERK signaling occurred as a result of activation of HER family receptors as evidenced by induction of HER receptors dimerization and phosphorylation, increased expression of HER3 and binding of adaptor molecules to HER2 and HER3. The activation of ERK was prevented with either MEK inhibitors or anti-HER2 monoclonal antibodies and tyrosine kinase inhibitors. Combined administration of PI3K inhibitors with either HER2 or MEK inhibitors resulted in decreased proliferation, enhanced cell death and superior anti-tumor activity compared with single agent PI3K inhibitors. Our findings indicate that PI3K inhibition in HER2-overexpressing breast cancer activates a new compensatory pathway that results in ERK dependency. Combined anti-MEK or anti-HER2 therapy with PI3K inhibitors may be required in order to achieve optimal efficacy in HER2-overexpressing breast cancer. This approach warrants clinical evaluation.     

The Role of Mammalian Target of Rapamycin (mTOR) Inhibition in the Treatment of Advanced Breast Cancer

Endocrine therapy (ET) with aromatase inhibitors (AIs) has become the standard of care for postmenopausal women with hormone-receptor–positive (HR⁺) advanced breast cancer (ABC); however, progression following initial treatment remains a major clinical challenge given the large patient population, many of whom develop progressive disease. There is an unmet need for treatment strategies that can overcome endocrine resistance. Growth factor-mediated signaling pathways, such as the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway, contribute to estrogen-independent growth that may lead to endocrine resistance. Preclinical studies have demonstrated that the use of mTOR inhibitors, such as everolimus and temsirolimus, is a promising strategy to potentially enhance endocrine sensitivity in ABC. This review will focus on the current ET options for women with HR⁺ ABC who have progressed on prior AI therapy, the role of mTOR-mediated signaling in breast cancer, and the clinical evidence supporting the use of mTOR inhibitors.     

PI3K/Akt/mTOR inhibitors in breast cancer

Activation of the phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is common in breast cancer. There is preclinical data to support inhibition of the pathway, and phase I to III trials involving inhibitors of the pathway have been or are being conducted in solid tumors and breast cancer. Everolimus, an mTOR inhibitor, is currently approved for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. In this review, we summarise the efficacy and toxicity findings from the randomised clinical trials, with simplified guidelines on the management of potential adverse effects. Education of healthcare professionals and patients is critical for safety and compliance. While there is some clinical evidence of activity of mTOR inhibition in HR-positive and HER2-positive breast cancers, the benefits may be more pronounced in selected subsets rather than in the overall population. Further development of predictive biomarkers will be useful in the selection of patients who will benefit from inhibition of the PI3K/Akt/mTOR (PAM) pathway.KEYWORDS : Breast cancer, phosphoinositide 3 kinase (PI3K)/Akt/ mammalian target of rapamycin (mTOR), everolimus     

Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway

Background

Most targeted anticancer therapies, as well as cytotoxic and radiation therapies, are encumbered by the development of secondary resistance by cancer cells. Resistance is a complex phenomenon involving multiple mechanisms, including activation of signaling pathways such as phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR). Novel strategies to overcome resistance by targeting these signaling pathways are being evaluated.

Methods

PubMed and key cancer congress abstracts were searched until July 2012 for preclinical and clinical data relating to the PI3K/AKT/mTOR pathway and anticancer treatment resistance, and use of PI3K/AKT/mTOR inhibitors in resistant cancer cell lines and patient populations.

Results

Activation of the PI3K/AKT/mTOR pathway is frequently implicated in resistance to anticancer therapies, including biologics, tyrosine kinase inhibitors, radiation, and cytotoxics. As such, inhibitors of the PI3K/AKT/mTOR pathway are being rapidly evaluated in preclinical models and in clinical studies to determine whether they can restore therapeutic sensitivity when given in combination. In breast cancer, non-small-cell lung cancer, and glioblastoma, we find compelling preclinical evidence to show that inhibitors of PI3K or mTOR can restore sensitivity in resistant cells. Although clinical evidence is less mature, a recent Phase III study with the mTORC1 inhibitor everolimus in patients with advanced breast cancer resistant to aromatase inhibition and several Phase I/II studies with PI3K inhibitors demonstrate proof-of-concept, warranting future clinical evaluation.

Conclusion

Current preclinical and clinical evidence suggest that inhibitors of the PI3K/AKT/mTOR pathway could have utility in combination with other anticancer therapies to circumvent resistance by cancer cells. Multiple clinical studies are ongoing.     

PI3K pathway inhibitors for the treatment of brain metastases with a focus on HER2+ breast cancer

The incidence of breast cancer brain metastases has increased in recent years, largely due to improved control of systemic disease with human epidermal growth factor receptor 2 (HER2)-targeted agents and the inability of most of these agents to efficiently cross the blood–blood barrier (BBB) and control central nervous system disease. There is, therefore, an urgent unmet need for treatments to prevent and treat HER2+ breast cancer brain metastases (BCBMs). Aberrant activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway is frequently observed in many cancers, including primary breast tumors and BCBMs. Agents targeting key components of this pathway have demonstrated antitumor activity in diverse cancers, and may represent a new treatment strategy for BCBMs. In preclinical studies, several inhibitors of PI3K and mTOR have demonstrated an ability to penetrate the BBB and down-regulate PI3K signaling, indicating that these agents may be potential therapies for brain metastatic disease. The PI3K inhibitor buparlisib (BKM120) and the mTOR inhibitor everolimus (RAD001) are currently under evaluation in combination with trastuzumab in patients with HER2+ BCBMs.     

Genetically engineered mouse models of PI3K signaling in breast cancer

Breast cancer is the most common type of cancer in women. A substantial fraction of breast cancers have acquired mutations that lead to activation of the phosphoinositide 3-kinase (PI3K) signaling pathway, which plays a central role in cellular processes that are essential in cancer, such as cell survival, growth, division and motility. Oncogenic mutations in the PI3K pathway generally involve either activating mutation of the gene encoding PI3K (PIK3CA) or AKT (AKT1), or loss or reduced expression of PTEN. Several kinases involved in PI3K signaling are being explored as a therapeutic targets for pharmacological inhibition. Despite the availability of a range of inhibitors, acquired resistance may limit the efficacy of single-agent therapy. In this review we discuss the role of PI3K pathway mutations in human breast cancer and relevant genetically engineered mouse models (GEMMs), with special attention to the role of PI3K signaling in oncogenesis, in therapeutic response, and in resistance to therapy. Several sophisticated GEMMs have revealed the cause-and-effect relationships between PI3K pathway mutations and mammary oncogenesis. These GEMMs enable us to study the biology of tumors induced by activated PI3K signaling, as well as preclinical response and resistance to PI3K pathway inhibitors.     

PI3K inhibitors in trastuzumab-resistant HER2-positive breast cancer cells with PI3K pathway alterations

The activation of the PI3K signaling pathway resulting from genetic alterations induces carcinogenesis and resistance to anticancer therapies. Breast cancer is a major malignancy that is associated with dysregulation of the PI3K signaling pathway. PIK3CA mutations and PTEN loss occur in every subtype of breast cancer. PI3K inhibitors are being evaluated in breast cancer after the success of an alpha isoform-specific PI3K inhibitor in estrogen receptor (ER)-positive/HER2-negative metastatic breast cancer. Some preclinical data indicate the potential for PI3K/mTOR targeting in combination with trastuzumab for HER2-positive breast cancer with or without expression of the estrogen receptor. However, the role of this therapy in HER2-positive breast cancer with PIK3CA mutations and/or PTEN loss remains unclear. We examined three HER2-positive, ER-negative breast cancer cell lines to determine the efficacy of a novel alpha isoform-specific PI3K inhibitor in combination with trastuzumab. The results indicated that this combination was effective in PIK3CA-mutant or PTEN-deficient breast cancer cells by inducing apoptosis and inhibiting the expression of downstream proteins. PTEN loss by siRNA modulation in parental HER2-positive cancer cells with PI3K signaling pathway alterations could not confer resistance to alpelisib or GDC-0077 plus trastuzumab. We selected the CK-MB-1 cell line without alterations in the PI3K pathway to demonstrate that PI3K inhibitors plus trastuzumab represented a biomarker-specific treatment. In vivo effects of alpelisib plus trastuzumab were tested and confirmed in a mouse model, showing the combination strategy offered the best opportunity to achieve tumor volume reduction. With known safety profiles, this cytotoxic chemotherapy-free regimen warrants further attention as a biomarker-driven strategy for treating HER2-positive breast cancer.     

Targeting PIK3CA Alterations in Hormone Receptor-Positive,Human Epidermal Growth Factor Receptor-2–Negative Advanced Breast Cancer: New Therapeutic Approaches and Practical Considerations

The phosphatidylinositol-3-kinase (PI3K) pathway is frequently dysregulated in human breast cancer. Approximately 30% of all patients with breast cancer will carry mutations of the PIK3CA gene, which encodes the PI3K catalytic subunit isoform p110α. Mutations in PIK3CA have been associated with resistance to endocrine therapy, HER2-directed therapy, and cytotoxic therapy. Early trials of pan-PI3K inhibitors showed little treatment benefit as monotherapy owing to disease resistance arising through enhanced estrogen receptor pathway signaling. Combining PI3K inhibition with endocrine therapy can help overcome resistance. Clinical trials of pan-PI3K inhibitors combined with endocrine therapy demonstrated modest clinical benefits but challenging toxicity profiles, facilitating the development of more selective PI3K-targeting agents. More recent trials of isoform-specific PI3K inhibitors in patients with PIK3CA mutations have shown promising clinical efficacy with a predictable, manageable safety profile. In the present review, we discuss the clinical relevance of mutations of PIK3CA and their potential use as a biomarker to guide treatment choices in patients with HR⁺ HER2⁻ advanced breast cancer.     

Down-regulation of phosphatidylinositol 3'-kinase/AKT/molecular target of rapamycin metabolic pathway by primary letrozole-based therapy in human breast cancer.

PURPOSE: The phosphatidylinositol 3'-kinase (PI3K)/AKT/molecular target of rapamycin (mTOR) pathway is involved in the development of tumor resistance to endocrine therapy in breast cancer cell lines and represents an attractive target for pharmacologic intervention. However, the effects of endocrine therapy with aromatase inhibitors on in vivo expression of this signaling cascade, and its relation to tumor response and patient outcome, is unknown. EXPERIMENTAL DESIGN: PI3K, phospho-AKT (pAKT) and phospho-mTOR were assessed by immunohistochemistry on tumor specimens collected at baseline and after 6 months of treatment in 113 elderly breast cancer patients consecutively enrolled in a randomized phase II trial of primary letrozole therapy and letrozole associated with metronomic cyclophosphamide. RESULTS: Basal expression of the pathway was not significantly correlated with response or patient outcome. Both letrozole alone and letrozole with cyclophosphamide resulted in a significant reduction of PI3K expression (P = 0.02 and P < 0.005, respectively) and phospho-mTOR expression (P = 0.0001 and P = 0.0001, respectively). pAKT showed no change in the letrozole arm, whereas it was significantly decreased in the letrozole plus cyclophosphamide arm (P < 0.005). pAKT expression reduction was associated with a greater response rate (P = 0.05) and greater reduction in Ki67 expression (P = 0.05). Phospho-mTOR expression reduction was associated with a significantly longer disease-free survival in a multivariate analysis (P = 0.02). CONCLUSIONS: Letrozole inhibits key molecules in the PI3K pathway that are important targets of new drugs being developed to overcome resistance. Changes in these molecules may have prognostic significance. These results should be taken into account when planning prospective trials testing up-front aromatase inhibitor with drugs targeting the PI3K/AKT/mTOR signaling pathway.     

The next era of treatment for hormone receptor-positive,HER2-negative advanced breast cancer: Triplet combination-based endocrine therapies

Until recently, the standard of care for hormone receptor-positive (HR+) breast cancer was single-agent endocrine therapy, which aims to prevent estrogen receptor signaling. This therapeutic strategy has extended survival without the toxicity associated with chemotherapy, but primary endocrine therapy resistance is common, and secondary resistance develops over time. Adjunct downstream inhibition of the cyclin-dependent kinase (CDK)4/6 pathway, intended to delay and prevent endocrine therapy resistance, has further extended progression-free survival in patients receiving endocrine therapy; however, resistance still eventually develops in these patients. Addition of phosphatidylinositol-3 kinase (PI3K) or mammalian target of rapamycin (mTOR) inhibitors to combined CDK4/6 and endocrine inhibitor regimens may help prolong CDK4/6 inhibitor sensitivity. Early trials combining CDK4/6 inhibitors, PI3K or mTOR inhibitors, and endocrine therapy have shown encouraging signs of clinical activity. However, further research is needed to help understand the extent of treatment benefit from triplet therapy and where this strategy will fit in the treatment sequence for patients with HR+ breast cancer.     

Reduced PTEN expression in breast cancer cells confers susceptibility to inhibitors of the PI3 kinase/Akt pathway.

The PTEN protein is a lipid phosphatase with putative tumor suppressing abilities, including inhibition of the PI3K/Akt signaling pathway. Inactivating mutations or deletions of the PTEN gene, which result in hyper-activation of the PI3K/Akt signaling pathway, are increasingly being reported in human malignancies, including breast cancer, and have been related to features of poor prognosis and resistance to chemotherapy and hormone therapy. Prior studies in different tumor models have shown that, under conditions of PTEN deficiency, the PI3K/Akt signaling pathway becomes a fundamental proliferative and survival pathway, and that pharmacological inhibition of this pathway results in tumor growth inhibition. This study aimed to explore further this hypothesis in breast cancer cells. To this end, we have determined the growth response to inhibition of the PI3K/Akt signaling pathway in a series of breast cancer cell lines with different PTEN levels. The PTEN-negative cell line displayed greater sensitivity to the growth inhibitory effects of the PI3K inhibitor, LY294002 and rapamycin, an inhibitor of the PI3K/Akt downstream mediator mTOR, compared with the PTEN-positive cell lines. To determine whether or not these differences in response are specifically due to effects of PTEN, we developed a series of cell lines with reduced PTEN protein expression compared with the parental cell line. These reduced PTEN cells demonstrated an increased sensitivity to the anti-proliferative effects induced by LY294002 and rapamycin compared with the parental cells, which corresponded to alterations in cell cycle response. These findings indicate that inhibitors of mTOR, some of which are already in clinical development (CCI-779, an ester of rapamycin), have the potential to be effective in the treatment of breast cancer patients with PTEN-negative tumors and should be evaluated in this setting.     

ErbB2-overexpressing human mammary carcinoma cells display an increased requirement for the phosphatidylinositol 3-kinase signaling pathway in anchorage-independent growth.

The proto-oncogene ErbB2 is known to be amplified and to play an important role in the development of about one-third of human breast cancers. Phosphatidylinositol 3-kinase (PI3K), which is often activated in ErbB2-overexpressing breast cancer cells, is known to regulate cell proliferation and cell survival. Selective inhibitors of the PI3K pathway were used to assess the relevance of PI3K signaling in the anchorage-independent growth of a series of human mammary carcinoma cell lines. Wortmannin, LY294002, and rapamycin at concentrations that did not affect MAPK phosphorylation but substantially inhibited PI3K, Akt, and p70(S6K) significantly suppressed the soft agar growth of tumor cell lines that overexpress ErbB2 but not the growth of tumor lines with low ErbB2 expression. A similar growth inhibition of ErbB2-overexpressing carcinoma lines was observed when a dominant negative p85(PI3K) mutant was introduced into these cells. Forced expression of ErbB2 in breast cancer lines originally expressing low ErbB2 levels augmented receptor expression and sensitized those lines to LY294002- and rapamycin-mediated inhibition of colony formation. Furthermore, treatment with LY294002 resulted in the selective increase of cyclin-dependent kinase inhibitors p21(Cip1) or p27(Kip1) and suppression of cyclin E-associated Cdk2 kinase activity in ErbB2-overexpressing lines, which may account for their hypersensitivity toward inhibitors of the PI3K pathway in anchorage-independent growth. Our results indicate that the PI3K/Akt/p70(S6K) pathway plays an enhanced role in the anchorage-independent growth of ErbB2-overexpressing breast cancer cells, therefore providing a molecular basis for the selective targeting of this signaling pathway in the treatment of ErbB2-related human breast malignancies.     

PI3K/AKT/mTOR通路及其抑制剂在乳腺癌中的应用现状

磷脂酰肌醇3-激酶（phosphoinositide 3-kinase,PI3K）/蛋白激酶B（protein kinase B,AKT）/哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin,mTOR）信号转导通路在多种肿瘤中异常激活,参与肿瘤细胞增殖、分化和凋亡等生命过程的调控,是抗肿瘤药物研发的重要靶点。对目前已应用于乳腺癌临床或处于临床试验阶段的PI3K/AKT/mTOR信号通路抑制剂进行归纳,并综述该通路抑制剂的联合用药策略,以期为不同亚型乳腺癌提供个体化靶向治疗方案。     

Will PI3K pathway inhibitors be effective as single agents in patients with cancer?

The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) axis regulates essential cellular functions including cell survival, proliferation, metabolism, migration, and angiogenesis. The PI3K pathway is activated in human cancers by mutation, amplification, and deletion of genes encoding components of this pathway. The critical role of PI3K in cancer has led to the development of drugs targeting the effector mechanisms of this signaling network. Recent studies have shown that inhibition at multiple levels of the PI3K pathway results in FOXO-dependent feedback reactivation of several receptor tyrosine kinases (RTKs) which, in turn, limit the sustained inhibition of this pathway and attenuates the action of therapeutic antagonists. This suggests that if used as single agents, PI3K pathway inhibitors may have limited clinical activity. We propose herein that to successfully target the output of the PI3K pathway in cancer cells, combination therapies that hinder these compensatory mechanisms should be used. Thus, combination therapies that target RTKs, PI3K, and mTOR activities may be required to maximize the clinical benefit derived from treatment with these inhibitors.     

PIK3CA mutation, but not PTEN loss of function, determines the sensitivity of breast cancer cells to mTOR inhibitory drugs

The phosphatidylinositol 3-kinase (PI3K) pathway is commonly activated in breast cancers due to frequent mutations in PIK3CA, loss of expression of PTEN or over-expression of receptor tyrosine kinases. PI3K pathway activation leads to stimulation of the key growth and proliferation regulatory kinase mammalian target of rapamycin (mTOR), which can be inhibited by rapamycin analogues and by kinase inhibitors; the effectiveness of these drugs in breast cancer treatment is currently being tested in clinical trials. To identify the molecular determinants of response to inhibitors that target mTOR via different mechanisms in breast cancer cells, we investigated the effects of pharmacological inhibition of mTOR using the allosteric mTORC1 inhibitor everolimus and the active-site mTORC1/mTORC2 kinase inhibitor PP242 on a panel of 31 breast cancer cell lines. We demonstrate here that breast cancer cells harbouring PIK3CA mutations are selectively sensitive to mTOR allosteric and kinase inhibitors. However, cells with PTEN loss of function are not sensitive to these drugs, suggesting that the functional consequences of these two mechanisms of activation of the mTOR pathway are quite distinct. In addition, a subset of HER2-amplified cell lines showed increased sensitivity to PP242, but not to everolimus, irrespective of the PIK3CA/PTEN status. These selective sensitivities were confirmed in more physiologically relevant three-dimensional cell culture models. Our findings provide a rationale to guide selection of breast cancer patients who may benefit from mTOR inhibitor therapy and highlight the importance of accurately assessing the expression of PTEN protein and not just its mutational status.     

Two hits are better than one: targeting both phosphatidylinositol 3-kinase and mammalian target of rapamycin as a therapeutic strategy for acute leukemia treatment

Phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) are two key components of the PI3K/Akt/mTOR signaling pathway. This signal transduction cascade regulates a wide range of physiological cell processes, that include differentiation, proliferation, apoptosis, autophagy, metabolism, motility, and exocytosis. However, constitutively active PI3K/Akt/mTOR signaling characterizes many types of tumors where it negatively influences response to therapeutic treatments. Hence, targeting PI3K/Akt/mTOR signaling with small molecule inhibitors may improve cancer patient outcome. The PI3K/Akt/mTOR signaling cascade is overactive in acute leukemias, where it correlates with enhanced drug-resistance and poor prognosis. The catalytic sites of PI3K and mTOR share a high degree of sequence homology. This feature has allowed the synthesis of ATP-competitive compounds targeting the catalytic site of both kinases. In preclinical models, dual PI3K/mTOR inhibitors displayed a much stronger cytotoxicity against acute leukemia cells than either PI3K inhibitors or allosteric mTOR inhibitors, such as rapamycin. At variance with rapamycin, dual PI3K/mTOR inhibitors targeted both mTOR complex 1 and mTOR complex 2, and inhibited the rapamycin-resistant phosphorylation of eukaryotic initiation factor 4E-binding protein 1, resulting in a marked inhibition of oncogenic protein translation. Therefore, they strongly reduced cell proliferation and induced an important apoptotic response. Here, we reviewed the evidence documenting that dual PI3K/mTOR inhibitors may represent a promising option for future targeted therapies of acute leukemia patients.