Targeting the PI3K signaling pathway in cancer

doi:10.1016/j.gde.2009.11.002

Current Opinion in Genetics & Development

Volume 20, Issue 1, February 2010, Pages 87-90

https://doi.org/10.1016/j.gde.2009.11.002 Get rights and content

The phosphoinositide 3-kinase (PI3K) pathway is activated in a variety of different human cancers, and inhibitors of this pathway are under active development as anti-cancer therapeutics. In this review, we discuss the data supporting the use of PI3K pathway inhibitors in genetically and clinically defined cancers. This review focuses on their efficacy as single agents and in combination with other targeted therapies, specifically those targeting the MEK–ERK signaling pathway.

Introduction

The phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that propagate intracellular signaling cascades regulating a wide range of cellular processes. PI3K phosphorylates the 3′-OH group on phosphatidylinositols in the plasma membrane. This leads to recruitment of the protein Ser/Thr-kinase, AKT, to the cell membrane where it becomes activated. The PI3K/AKT signaling cascade is crucial in cancer as it promotes cell survival and growth (for reviews, see references [1, 2, 3, 4]). PI3K–AKT signaling is activated in cancers by several different mechanisms [2]. Somatic mutations in PIK3CA, the gene encoding the p110α catalytic subunit, have been identified in a variety of solid tumors [5], and they are most frequently observed in two hotspots: the helical domain (E545K and E542K) and the kinase domain (H1047R). These mutations have been shown to be transforming in vitro and in vivo [6, 7, 8]. Receptor tyrosine kinases, such as EGFR, HER2, and PDGFR, that are activated in many cancers, also engage the PI3K pathway. Furthermore, p110 has been shown to bind RAS directly, thereby providing a potential biochemical link between RAS and PI3K signaling. PTEN, a phosphatase that degrades the phosphoinositide products of PI3K, is frequently lost in many different cancer types, including prostate, breast, and brain cancers [9]. Lastly, activating mutations in AKT have also been recently reported in breast cancers [10]. Thus, the PI3K signaling pathway is speculated to be one of the crucial core pathways for cancer development and maintenance (for review, see Engelman, Nature Cancer Review) [2]. The ubiquitous nature of PI3K pathway activation in cancer suggests that PI3K, AKT, and other components of this pathway may be attractive targets for cancer therapy, and multiple PI3K pathway inhibitors are now under active clinical development.

Section snippets

PI3K pathway in tumor development, maintenance and acquired resistance

Recent genetic studies have provided additional mechanistic insights into the role of PI3K pathway in various aspects of cancer progression and response to treatment. Murine established lung cancers induced by mutant PIK3CA (H1047R) are quite highly sensitive to PI3K inhibitors. In addition, preclinical studies demonstrate that breast cancer cell lines with PIK3CA mutations are sensitive to PI3K–mTOR and AKT inhibitors [11•, 12•]. These studies provide a clear preclinical rationale for the

Activation of ERBB3 and PI3K signaling as a mechanism of acquired resistance to TKIs targeting EGFR and HER2

Tyrosine kinase inhibitors (TKIs) of EGFR and HER2 are active in subsets of lung and breast cancers. In particular, lung cancers that harbor the EGFR kinase domain mutations respond to small molecule EGFR inhibitors such as gefitinib and erlotinib. Unfortunately, after a median duration of response of 10–12 months, all cancers invariably develop resistance [16]. The most common mechanism of acquired resistance is the development of a secondary EGFR mutation, T790M, which increases the affinity

Concurrent PI3K related genetic alterations in cancer and implication for therapy

It is intriguing that PIK3CA activating mutations are often present with other concurrent genetic alterations that activate the PI3K pathway. PTEN loss (breast, endometrium, and colon), RAS activating mutations (colon), and HER2 amplifications (breast) are frequently found with PIK3CA mutations in multiple cancer types [23]. One likely explanation is that the sole activation of the PI3K pathway is not sufficient for transformation in many cancer types. Activation of non-overlapping transduction

Single-agent PI3K inhibition therapy and combination therapy in different genetically defined cancers

With recent availability of PI3K pathway inhibitors, there have been strong ongoing efforts in examining the activity of these agents used either singly or in combination with other targeted therapeutics in the treatment of various genetically defined cancers. As discussed above, we recently observed that a highly specific PI3K–mTOR inhibitor can dramatically shrink p110 H1047R driven lung adenocarcinomas. In addition, PI3K–mTOR inhibitors, as single agents, can also cause dramatic apoptosis in

Future directions

With the development of multiple inhibitors that target the PI3K pathways (such as the p110 inhibitors and AKT inhibitors), it will be important to understand the role of PI3K–AKT dependent and independent pathways in cancer maintenance and progression in specific cancer types. These findings will quickly be translated into generating better strategies to optimize their use in cancer clinical trials. In this era of personalized medicine in which cancers are genotyped for the most common genetic

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

References (32)

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Mutant PIK3CA promotes cell growth and invasion of human cancer cells
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M.S. Cragg et al.
Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 mimetics
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Targeting PI3K signalling in cancer: opportunities, challenges and limitations
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Oncogenic PI3K and its role in cancer
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PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer

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A transforming mutation in the pleckstrin homology domain of AKT1 in cancer

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NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations

Cancer Res

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Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to Akt signaling

PLoS One

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Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers

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Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance

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Targeting the PI3K signaling pathway in cancer

Introduction

Section snippets

PI3K pathway in tumor development, maintenance and acquired resistance

Activation of ERBB3 and PI3K signaling as a mechanism of acquired resistance to TKIs targeting EGFR and HER2

Concurrent PI3K related genetic alterations in cancer and implication for therapy

Single-agent PI3K inhibition therapy and combination therapy in different genetically defined cancers

Future directions

References and recommended reading

Cancer Cell

Science

PLoS Med

The phosphoinositide 3-kinase pathway

Science

Targeting PI3K signalling in cancer: opportunities, challenges and limitations

Nat Rev Cancer

The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism

Nat Rev Genet

The phosphatidylinositol 3-kinase AKT pathway in human cancer

Nat Rev Cancer

Oncogenic mutations of PIK3CA in human cancers

Cell Cycle

Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells

Cancer Res

Oncogenic PI3K and its role in cancer

Curr Opin Oncol

PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer

Science

A transforming mutation in the pleckstrin homology domain of AKT1 in cancer

Nature

NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations

Cancer Res

Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to Akt signaling

PLoS One

Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers

Nat Med

Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance

Cancer Res