PTEN-deficient cancers depend on PIK3CB

Abstract

Deregulation of the PI3K signaling pathway is observed in many human cancers and occurs most frequently through loss of PTEN phosphatase tumor suppressor function or through somatic activating mutations in the Class IA PI3K, PIK3CA. Tumors harboring activated p110␣, the protein product of PIK3CA, require p110␣ activity for growth and survival and hence are expected to be responsive to inhibitors of its lipid kinase activity. Whether PTEN-deficient cancers similarly depend on p110␣ activity to sustain activation of the PI3K pathway has been unclear. In this study, we used a single-vector lentiviral inducible shRNA system to selectively inactivate the three Class IA PI3Ks, PIK3CA, PIK3CB, and PIK3CD, to determine which PI3K isoforms are responsible for driving the abnormal proliferation of PTEN-deficient cancers. Down-regulation of PIK3CA in colorectal cancer cells harboring mutations in PIK3CA inhibited downstream PI3K signaling and cell growth. Surprisingly, PIK3CA depletion affected neither PI3K signaling nor cell growth in 3 PTEN-deficient cancer cell lines. In contrast, down-regulation of the PIK3CB isoform, which encodes p110␤, resulted in pathway inactivation and subsequent inhibition of growth in both cell-based and in vivo settings. This essential function of PIK3CB in PTEN-deficient cancer cells required its lipid kinase activity. Our findings demonstrate that although p110␣ activation is required to sustain the proliferation of established PIK3CA-mutant tumors, PTEN-deficient tumors are dependent instead on p110␤ signaling. This unexpected finding demonstrates the need to tailor therapeutic approaches to the genetic basis of PI3K pathway activation to achieve optimal treatment response.

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“…Other studies support that tumors that have loss of PTEN are selectively dependent upon the β-isoform of PI3K (PIK3CB). 64,65 Consistent with this biochemical finding, preclinical studies have shown a positive correlation between loss of PTEN and sensitivity to selective inhibitors of PI3Kβ. 66 Phase I trials of two different PI3K-selective inhibitors are currently enrolling patients (NCT01673737, NCT01458067).…”

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“…In addition, however, p110b plays a necessary and positive role in certain tumors driven by PTEN loss (Jia et al 2008;Torbett et al 2008;Wee et al 2008). Similar genetic behavior has previously been noted for the gene encoding the p85 adapter protein (Mauvais-Jarvis et al 2002;Ueki et al 2002Ueki et al , 2003Taniguchi et al 2006); p85 has a dual role as a negative regulator of the ground-state activity of p110 catalytic kinase subunits while also functioning to dock the kinases to activating receptors.…”

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“…ETS domain-containing transcription factor ERF is a transcription repressor of ETS2 promoter which is regulated by MAPK1/ERK2 phosphorylation (Sgouras et al, 1995). PIK3CB plays a role in phosphatidylinositol (PI) signaling pathway (Wee et al, 2008;Dbouk et al, 2010) through interacting with AKT1, PTEN, and PIK3R1 (Figure 2). Up-regulation of this protein may affect the downstream signaling cascade of PI signaling pathway (Wee et al, 2008), which may promote cancer cell growth and differentiation.…”

“…PIK3CB plays a role in phosphatidylinositol (PI) signaling pathway (Wee et al, 2008;Dbouk et al, 2010) through interacting with AKT1, PTEN, and PIK3R1 (Figure 2). Up-regulation of this protein may affect the downstream signaling cascade of PI signaling pathway (Wee et al, 2008), which may promote cancer cell growth and differentiation. Casein kinase (CK) II subunit alpha is involved in cell proliferation.…”