Background: Loss of PTEN represents one of the most common disruptions of tumor suppressor activity in the progression of human neoplasia. There are no established precision medicine approaches defined in PTEN-deficient neoplasms which include prostate, breast, glioblastoma (GBM) and uterine cancers. In PTEN-mutant prostate cancer cells, the PI3K/Akt pathway collaborates with BCL-XL specifically, to regulate the apoptotic threshold (Ren, MCR 2016). Whereas single agent PI3K/Akt inhibitors are ineffective in inducing cell death, combined inhibition of PI3K/Akt and BCL-XL in PTEN-mutant prostate cancer cells results in synergistic apoptosis suggesting a novel therapeutic strategy with translational potential in this important subset of disease.

Hypothesis: We hypothesized that synthetic lethality following combinatorial PI3K/BCL-XL inhibition is conserved across the range of PTEN-mutant cancers.

Methods: PTEN-mutant cell lines (ATCC), validated for PTEN-loss and p-Akt expression, were assessed in apoptosis (cleaved Parp) and cell-viability assays following combined PI3K (Buparlisib, SelleckChem) and BCL-XL (A-1331852, AbbVie) inhibition (1µM each, 24h). Since MEK signaling has been associated with resistance to PI3K pathway inhibition, p-Erk was profiled as a candidate marker of resistance. The contribution of MEK signaling to the apoptotic threshold in p-Erk expressing PTEN-mutant cells was tested with pharmacological MEK inhibition (Trametinib, SelleckChem; 1,3,5 µM 48h) in combination.

Results:

MEK signaling and PI3K/BCL-XL inhibition in PTEN-mutant cancers

Source Cell line PTEN p-Akt p-Erk Synergistic Apoptosis with PI3K / BCL-XL inhibition Loss of cell viability p-Erk suppression with MEK inhibition Apoptosis with concomitant MEK inhibition 
Prostate PC3 Absent Present Absent Yes Yes N/A N/A 
Prostate LNCaP Absent Present Absent Yes Yes N/A N/A 
Prostate C4-2B Absent Present Absent Yes Yes N/A N/A 
Breast ZR-75-1 Absent Present Weak Yes Yes N/A N/A 
Uterine SK-UT-1 Absent Present Present No No Yes Yes 
GBM A-172 Absent Present Present No No Yes No 
Cervix C33-A Absent Present Present No No 
Source Cell line PTEN p-Akt p-Erk Synergistic Apoptosis with PI3K / BCL-XL inhibition Loss of cell viability p-Erk suppression with MEK inhibition Apoptosis with concomitant MEK inhibition 
Prostate PC3 Absent Present Absent Yes Yes N/A N/A 
Prostate LNCaP Absent Present Absent Yes Yes N/A N/A 
Prostate C4-2B Absent Present Absent Yes Yes N/A N/A 
Breast ZR-75-1 Absent Present Weak Yes Yes N/A N/A 
Uterine SK-UT-1 Absent Present Present No No Yes Yes 
GBM A-172 Absent Present Present No No Yes No 
Cervix C33-A Absent Present Present No No 

Conclusions: Synthetic lethality in PTEN-mutant tumor cells with PI3K/BCL-XL inhibition was confined to tumor cells without active MEK signaling. MEK inhibition inconsistently overcomes resistance to therapy suggesting heterogeneity of survival pathways in p-erk expressing PTEN-deficient tumors. These data have implications for precision medicine approaches in PTEN-deficient tumors as absence of p-Erk expression may predict for a responsive phenotype.

Citation Format: Raghav Joshi, Wenying Ren, Paul Mathew. MEK signaling marks resistance to synthetic lethality induced by PI3K/Akt and BCL-XL inhibition in PTEN-mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2162. doi:10.1158/1538-7445.AM2017-2162