PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer

Abstract

Combined MAPK/PI3K pathway inhibition represents an attractive, albeit toxic, therapeutic strategy in oncology. Since PTEN lies at the intersection of these two pathways, we investigated whether PTEN status determines the functional response to combined pathway inhibition. PTEN (gene, mRNA, and protein) status was extensively characterized in a panel of cancer cell lines and combined MEK/mTOR inhibition displayed highly synergistic pharmacologic interactions almost exclusively in PTEN-loss models. Genetic manipulation of PTEN status confirmed a mechanistic role for PTEN in determining the functional outcome of combined pathway blockade. Proteomic analysis showed greater phosphoproteomic profile modification(s) in response to combined MEK/mTOR inhibition in PTEN-loss contexts and identified JAK1/STAT3 activation as a potential mediator of synergistic interactions. Overall, our results show that PTEN-loss is a crucial determinant of synergistic interactions between MAPK and PI3K pathway inhibitors, potentially exploitable for the selection of cancer patients at the highest chance of benefit from combined therapeutic strategies.

Preclinical Evidence for Targeting PI3K/mTOR Signaling with Dual-Inhibitors as a Therapeutic Strategy against Cutaneous T-Cell Lymphoma

“…In addition, drug resistance for targeted therapies in PTEN-deficient tumors, such as with MAPK/ERK kinaseinhibitors, anti-estrogen drugs, EGFR inhibitors (Chappell et al, 2011;Dillon and Miller, 2014), can be prevented by combining treatments with PI3K/AKT/mTOR inhibitors (Brana et al, 2017;Philip et al, 2017). Indeed, PTEN-deficient lesions are significantly associated with increased sensitivity to PI3K/AKT/mTOR inhibitors in a wide range of tumor cell lines (Milella et al, 2017;Yang et al, 2013). Interestingly, in our study, the patient least responsive to PF-502 treatment (i.e., SS85) coincidentally had the highest expression level of the PTEN and LKB1 molecular brakes and a low level of S6RP phosphorylation upon stimulation with SDF-1.…”

mTOR Cross-Talk in Cancer and Potential for Combination Therapy

“…Recently, we also identified a novel cross-talk mechanism, by which pharmacologic or genetic inhibition of MEK restores PTEN expression, thus leading to cross-inhibition of downstream signaling through AKT and mTOR: more specifically, ERK-dependent upregulation of c-Jun and miR-25 leads to suppression of PTEN expression ( Figure 2 ) [ 77 ]. According to these results, our group demonstrated that, in twenty-nine cancer cell lines with different histological origin (melanoma, n = 7; Breast Cancer (BC), n = 6; Non-Small Cell Lung Cancer (NSCLC), n = 6; ColoRectal Cancer (CRC), n = 8; pancreatic adenocarcinoma, n = 2), PTEN-loss predicts synergistic interaction between MAPK (trametinib, dabrafenib) and PI3K/mTOR (everolimus, MK-2206, gedatolisib) pathway inhibitors, while combined MEK/mTOR inhibition results in a slightly additive/frankly antagonistic growth inhibitory response in PTEN-competent tumor cells ( Table 2 ) [ 78 ].…”

Patient-Derived Organoids from Multiple Colorectal Cancer Liver Metastases Reveal Moderate Intra-patient Pharmacotranscriptomic Heterogeneity

“…To explore the potential for more efficient growth inhibition of this multi-drug resistant and KRAS G12V mutated PDO, we designed a combination screen based on the strongest observed vulnerability: sensitivity to inhibition of the PI3K/AKT/mTOR pathway ( Figure 4C), which was associated with the apparent loss of PTEN expression ( Figure 4D). Combined mTOR or AKT inhibition with MEK inhibition may be synergistic in this genetic background (42,43), and both combination screens with everolimus (mTOR) or ipatasertib (AKT) plus trametinib suggested a synergistic negative effect on PDO viability, as evaluated by a zero interaction potency model ( Figure 4E). The differential response to idasanutlin in patient 18 was associated with heterozygous versus homozygous TP53 mutation status in the sensitive versus resistant PDOs, but all PDOs from this patient had a TP53 wild-type-like phenotype by gene expression.…”