Loss of function of the PTEN tumor suppressor gene leads to resistance to therapies targeting the Notch signaling pathway according to a mouse study presented at the 2016 Society of Gynecologic Oncology annual meeting, held in San Diego, March 19-22, 2016.
Loss of function of the PTEN (phosphatase and tensin homolog) tumor suppressor gene leads to resistance to therapies targeting the Notch signaling pathway according to a mouse study presented at the 2016 Society of Gynecologic Oncology annual meeting, held in San Diego, March 19-22, 2016.
If validated in human studies, the study, presented by Jean M. Hansen, DO, a fellow in the department of Gynecologic Oncology and Reproductive Medicine at MD Anderson Cancer Center, points to the utility of using PTEN mutational status as a predictive biomarker of response to Notch pathway-targeted therapies.
Dr. Hansen and her colleagues analyzed data from The Cancer Genome Atlas (TCGA) for gene expression, copy number, and exome sequences among 232 patients with endometrial cancer. Eighteen percent (42) had upregulation or amplification in either the Notch 2, Notch 3, or DLL3 genes whereas 82% had a loss-of-function mutation in these genes. Overall survival (OS) among patients with an upregulation or amplification in at least one of these genes was associated with a significantly shorter OS (P < .001). In a separate analysis of 407 patient samples, the top quartile of highest Notch3 expression was associated with poorer survival compared with the lowest quartile of Notch3 expression (P = .01).
“Our analysis of TCGA data showed that patients with upregulation and amplification of Notch 2 or 3 had worse survival outcomes as compared to patients with loss-of-function mutations in Notch 2 or 3,” Hansen told OncoTherapy Network. “Patients with high levels of Notch 3 expression had worse survival compared to those with low Notch 3 expression,” Hansen added.
Following the human sample analysis, the study authors analyzed outcomes in a mouse model of uterine cancer that had either a wild-type copy of PTEN or loss-of-function PTEN mutation. Inhibiting Notch3 using small interfering RNAs (siRNAs) in mice harboring a wild-type PTEN gene resulted in tumor shrinkage and less Ki-6700a marker of cell proliferation-compared to control mice treated with a control siRNA. The same experiment performed in a uterine cancer mouse model harboring a loss-of-function PTEN resulted in no tumor shrinkage when the mice were treated with siRNAs against Notch3 as compared to control siRNAs.
These results were consistent with experiments performed in vitro. Using uterine cancer cell lines, the study authors demonstrated that cell lines with a loss-of-function PTEN had increased viability following inhibition of Notch 2/3 compared to those cell lines with a wild PTEN gene.
The Notch cellular pathway functions during development and in determining cell fate in stem cells and progenitor cells. Mutations in the Notch pathway have been implicated in tumorigenesis. Notch 2 and 3 are receptors that bind to one of five Notch pathway ligands to control proliferation and survival. PTEN, part of the AKT/PI3K signaling pathway, has been previously shown to be regulated by the downstream targets of Notch.
“Based on our preclinical results, PTEN loss-of-function mutations in endometrial tumors should confer resistance to anti-Notch therapies,” said Hansen.
The team is now conducting more mouse model studies to understand whether restoring PTEN function may also restore sensitivity to Notch-inhibiting therapies. The researchers would also like to examine the PTEN status of patients on anti-Notch therapy trials.
Several cancer clinical trials testing Notch signaling inhibitors are currently in clinical trials including LY3039478 (Eli Lilly) and MEDI0639 (MedImmune), an anti-DLL4 antibody.