• What is PTEN?
  • PTEN in Colorectal Cancer
  • PTEN c.477G>T (R159S)
  • Clinical Trials

PTEN

PTEN (phosphatase and tensin homolog deleted on chromosome ten) is a lipid/protein phosphatase that plays a role in multiple cell processes, including growth, proliferation, survival, and maintenance of genomic integrity. PTEN acts as a tumor suppressor by negatively regulating the PI3K/AKT signaling pathway (Figure 1) via dephosphorylation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) at the cell membrane.

Cancer-associated alterations in PTEN often result in PTEN inactivation and thus increased activity of the PI3K-AKT pathway. Somatic mutations of PTEN occur in multiple malignancies, including gliomas, melanoma, prostate, endometrial, breast, ovarian, renal, and lung cancers. Germline mutations of PTEN lead to inherited hamartoma and Cowden syndrome (for reviews see Chalhoub and Baker 2009 and Maehama 2007). PTEN activity can also be lost through other mechanisms such as epigenetic changes or post-translational modifications (Leslie and Foti 2010). Immunochemistry is often used to detect changes in expression of PTEN in tumor tissues; low expression is thought to indicate loss of PTEN expression, which would result in increased activity of the PI3K-AKT pathway.

mapk-pk13.png

Figure 1.
Schematic of the MAPK and PI3K pathways. Growth factor binding to receptor tyrosine kinase results in activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR). The letter "K" within the schema denotes the tyrosine kinase domain.

Related Pathways

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. PTEN. My Cancer Genome https://www.padiracinnovation.org/content/disease/colorectal-cancer/pten/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

PTEN in Colorectal Cancer

PTEN mutations occur in 5–14% of colorectal cancers (Berg et al. 2010; COSMIC; De Roock et al. 2011; Dicuonzo et al. 2001). PTEN is a tumor suppressor gene, and loss of PTEN results in upregulation of the PI3K/ AKT pathway (Salmena et al., Cell 2008;133(3):403-414). PTEN loss of expression is observed with KRAS, BRAF, and PIK3CA mutations (De Roock et al. 2011; Laurent-Puig et al. 2009; Sartore-Bianchi et al. 2009).

Germline mutations in PTEN result in PTEN hamartoma tumor syndrome and are associated with increased risk for melanoma, breast, thyroid, endometrial, colorectal, and kidney cancer (Tan et al. 2012). George and Kopetz (2011) report that somatic PTEN mutations are weakly prognostic in stage 4 CRC patients. Research into the prognostic and predictive significance of PTEN mutations and other mechanisms for loss of PTEN expression is ongoing.

The role of PTEN loss in response to PI3K and mTOR inhibitors is being explored in clinical trials (De Roock et al. 2011; Markman et al. 2010). Preclinical studies have shown that p110α-specific PI3K inhibitors may be needed for treatment of PTEN-deficient cancers and that pan-PI3K inhibitors such as PX-866 may be effective in PIK3CA-mutated cancers and cancers showing PTEN loss (Courtney, Corcoran, and Engelman 2010). Likewise, in vitro studies have shown that inactivating mutations in the PTEN gene may confer sensitivity to PI3K-mTOR inhibitors [for review, see Courtney, Corcoran, and Engelman 2010) as well as FRAP/mTOR inhibitors (Neshat et al. 2001).

In retrospective studies, PTEN loss is associated with decreased sensitivity of colorectal cancer tumors to anti-EGFR antibodies (De Roock et al., 2011). PTEN loss is associated with lack of benefit of the anti-EGFR antibody, cetuximab (De Roock et al. 2011; Frattini et al. 2007; Laurent-Puig et al. 2009; Loupakis et al. 2009; Sartore-Bianchi et al. 2009).​

Contributors: Emily Chan, M.D., Ph.D.

Suggested Citation: Chan, E. 2015. PTEN in Colorectal Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/colorectal-cancer/pten/ (Updated June 18).

Last Updated: June 18, 2015

PTEN c.477G>T (R159S) Mutations in Colorectal Cancer

Properties
Location of mutation Exon 5
Frequency of PTEN mutations in colorectal cancer ​5–14% of colorectal cancers (Berg et al. 2010; COSMIC; De Roock et al. 2011; Dicuonzo et al. 2001)
Frequency of R159S mutations among PTEN-mutated colorectal cancers ~3% (COSMIC)
Implications for Targeted Therapeutics
Response to PI3K inhibitors Unknown at this timea
Response to dual PI3K/mTOR inhibitors Unknown at this timea
Response to dual FRAP/mTOR inhibitors Unknown at this timea
Response to AKT inhibitors Unknown at this time
Response to EGFR TKIs Unknown at this time
Response to anti-EGFR antibodies Unknown at this timeb

The R159S mutation results in the substitution of serine for arginine at position 159. This mutation occurs within exon 7, which encodes a portion of the C2 domain (Lee et al. 1999). C2 domains are known to be involved in targeting proteins to cell membranes.

a The role of PTEN loss in response to PI3K and mTOR inhibitors is being explored in clinical trials (De Roock et al. 2011; Markman et al. 2010). Preclinical studies have shown that p110α-specific PI3K inhibitors may be needed for treatment of PTEN-deficient cancers and that pan-PI3K inhibitors such as PX-866 may be effective in PIK3CA-mutated cancers and cancers showing PTEN loss (Courtney, Corcoran, and Engelman 2010). Likewise, in vitro studies have shown that inactivating mutations in the PTEN gene may confer sensitivity to PI3K-mTOR inhibitors [for review, see Courtney, Corcoran, and Engelman 2010] as well as FRAP/mTOR inhibitors (Neshat et al. 2001).

b In retrospective studies, PTEN loss is associated with decreased sensitivity of EGFR-mutated colorectal cancer tumors to anti-EGFR antibodies (De Roock et al., 2011). PTEN loss is associated with lack of benefit from the anti-EGFR antibody, cetuximab (De Roock et al. 2011; Frattini et al. 2007; Laurent-Puig et al. 2009; Loupakis et al. 2009; Sartore-Bianchi et al. 2009).

pten-r159s.png

Figure 1.
Schematic of R159S mutation. Functional domains of PTEN are depicted.

Contributors: Emily Chan, M.D., Ph.D.

Suggested Citation: Chan, E. 2017. PTEN c.477G>T (R159S) Mutations in Colorectal Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/colorectal-cancer/pten/24/ (Updated January 13).

Last Updated: January 13, 2017

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