Status of PI3K inhibition and biomarker development in cancer therapeutics

Markman, Benjamin; Atzori, Francesco; Peréz-García, José Manuel; Tabernero, Josep; Baselga, José

doi:10.1093/annonc/mdp347

Cited by 144 publications

(102 citation statements)

References 96 publications

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“…It was shown previously that genetic or pharmacological inhibition of one or more class 1 PI3K catalytic subunits in immortalized leukocytes and fibroblasts leads to functional compensation by the other subunits to preserve cell survival and proliferation (29). In line with this observation, results from cancer research suggest that a monotherapy using single subunit-selective PI3K antagonists might not be efficient to stop tumor growth due to functional compensation by other catalytic subunits (30). This further supports the applicability of therapies targeting p110β in patients with FXS, because it suggests that basic cell functions, such as mitosis and cell survival might not be affected by p110β-selective antagonists.…”

Section: Discussionmentioning

confidence: 79%

Excess Protein Synthesis in FXS Patient Lymphoblastoid Cells Can Be Rescued with a p110β-Selective Inhibitor

Groß

Bassell

2011

Mol Med

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Section: Discussionmentioning

confidence: 79%

Excess Protein Synthesis in FXS Patient Lymphoblastoid Cells Can Be Rescued with a p110β-Selective Inhibitor

Groß

Bassell

2011

Mol Med

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“…Class IB PI3Ks are activated by G-protein-coupled receptors only. [7,8] Class IA PI3Ks are the family member subtype involved in the PI3K/AKT/mTOR signaling cascade, whereas class IB PI3Ks are primarily involved in immune function and inflammation. [7] Class IA PI3Ks are heterodimers consisting of a catalytic subunit (p110) and a regulatory subunit (p85).…”

Section: Rapamycin (Mtor) Signaling Pathwaymentioning

confidence: 99%

“…[7,8] Class IA PI3Ks are the family member subtype involved in the PI3K/AKT/mTOR signaling cascade, whereas class IB PI3Ks are primarily involved in immune function and inflammation. [7] Class IA PI3Ks are heterodimers consisting of a catalytic subunit (p110) and a regulatory subunit (p85). [10,11] Each subunit can be encoded by three different genes: (i) regulatory, PIK3R1 (encodes p85α isoform), PIK3R2 (p85β), PIK3R3 (p85γ); and (ii) catalytic, PIK3CA (p110α), PIK3CB (p100β), and PIK3CC (p100δ).…”

Section: Rapamycin (Mtor) Signaling Pathwaymentioning

confidence: 99%

“…[38][39][40][41] Gain of function mutations in all three AKT genes have been identified in adult malignancies, including breast, colon, melanoma, and ovarian. [7,[42][43][44] No mutations have been identified in any AKT isoform in childhood cancer; however, chromosomal gains amplifying the AKT1 gene have been described recently in rare cases of childhood AML, T-cell ALL, and gliosarcoma. [45][46][47] Amplification of eIF4E, S6K1, and cyclin D have been reported in adult cancers, including breast and mantle cell lymphomas but not in pediatric tumors.…”

Section: Pi3k/akt/mtor Signaling In Cancermentioning

confidence: 99%

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Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

et al. 2012

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The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen.Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual-and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignanc...

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“…Cancers harboring mutations in the PIK3CA gene have emerged as among the most sensitive to single-agent PI3K inhibitors in several preclinical studies, although clinical activity to date has been mixed (3)(4)(5)(6). These gain-of-function mutations in the PI3KCA gene are found in a broad range of cancers, and they are highly enriched in breast cancer, where they are observed in 20-25% of cases (7). In addition, breast cancers with amplified HER2, which comprise ∼20% of all breast cancers, (8) are also particularly sensitive to PI3K inhibition (9)(10)(11).…”

mentioning

confidence: 99%

PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1

Ebi

Costa

Faber

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

182

163

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The PI3K pathway is genetically altered in excess of 70% of breast cancers, largely through PIK3CA mutation and HER2 amplification. Preclinical studies have suggested that these subsets of breast cancers are particularly sensitive to PI3K inhibitors; however, the reasons for this heightened sensitivity are mainly unknown. We investigated the signaling effects of PI3K inhibition in PIK3CA mutant and HER2 amplified breast cancers using PI3K inhibitors currently in clinical trials. Unexpectedly, we found that in PIK3CA mutant and HER2 amplified breast cancers sensitive to PI3K inhibitors, PI3K inhibition led to a rapid suppression of Rac1/p21-activated kinase (PAK)/protein kinase C-RAF (C-RAF)/ protein kinase MEK (MEK)/ERK signaling that did not involve RAS. Furthermore, PI3K inhibition led to an ERK-dependent up-regulation of the proapoptotic protein, BIM, followed by induction of apoptosis. Expression of a constitutively active form of Rac1 in these breast cancer models blocked PI3Ki-induced down-regulation of ERK phosphorylation, apoptosis, and mitigated PI3K inhibitor sensitivity in vivo. In contrast, protein kinase AKT inhibitors failed to block MEK/ERK signaling, did not upregulate BIM, and failed to induce apoptosis. Finally, we identified phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 (P-Rex1) as the PI(3,4,5)P3-dependent guanine exchange factor for Rac1 responsible for regulation of the Rac1/C-RAF/MEK/ERK pathway in these cells. The expression level of P-Rex1 correlates with sensitivity to PI3K inhibitors in these breast cancer cell lines. Thus, PI3K inhibitors have enhanced activity in PIK3CA mutant and HER2 amplified breast cancers in which PI3K inhibition down-regulates both the AKT and Rac1/ERK pathways. In addition, P-Rex1 may serve as a biomarker to predict response to single-agent PI3K inhibitors within this subset of breast cancers.

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Status of PI3K inhibition and biomarker development in cancer therapeutics

Cited by 144 publications

References 96 publications

Excess Protein Synthesis in FXS Patient Lymphoblastoid Cells Can Be Rescued with a p110β-Selective Inhibitor

Excess Protein Synthesis in FXS Patient Lymphoblastoid Cells Can Be Rescued with a p110β-Selective Inhibitor

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1

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