As observed at the individual level in previous studies, area-level socio-economic inequalities in health increased during the nineties, while general health improved.

Class IA PI3K pathway activation resulting from PTEN deficiency has been associated with lack of sensitivity of melanoma to BRAF kinase inhibitors. Although previous studies have shown synergistic activity when pan-PI3K inhibitors were combined with MAPK inhibitors in the treatment of melanoma exhibiting concurrent genetic abnormalities, overlapping adverse events in patients limit optimal dosing and clinical application. With the aim of specifically targeting PTEN-deficient cancers and minimizing the potential for on-target toxicity when inhibiting multiple PI3K isoforms, we developed a program to discover PI3Kb-selective kinase inhibitors and identified SAR260301 as a potent PI3Kb-selective, orally available compound, which is now in clinical development. Herein, we provide a detailed biological characterization of SAR260301, and show that this compound has outstanding biochemical and cellular selectivity for the PI3Kb isoform versus the a, d, and g isoforms and a large panel of protein and lipid kinases. We demonstrate that SAR260301 blocks PI3K pathway signaling preferentially in PTEN-deficient human tumor models, and has synergistic antitumor activity when combined with vemurafenib (BRAF inhibitor) or selumetinib (MEK inhibitor) in PTEN-deficient/BRAF-mutated human melanoma tumor models. Combination treatments were very well tolerated, suggesting the potential for a superior safety profile at optimal dosing using selective compounds to inhibit multiple signaling pathways. Together, these experiments provide a preclinical proof-of-concept for safely combining inhibitors of PI3Kb and BRAF or MEK kinase modulators to improve antitumor activity in PTEN-deficient/BRAF-mutant melanoma, and support the evaluation of SAR260301-based combinations in clinical studies. Mol Cancer Ther; 15(7); 1460-71. Ó2016 AACR.

KRASG12C is one of the most common mutations detected in non-small cell lung cancer (NSCLC) patients, and it is a marker of poor prognosis. The first FDA-approved KRASG12C inhibitors, sotorasib and adagrasib, have been an enormous breakthrough for patients with KRASG12C mutant NSCLC; however, resistance to therapy is emerging. The transcriptional coactivators YAP1/TAZ and the family of transcription factors TEAD1-4 are the downstream effectors of the Hippo pathway and regulate essential cellular processes such as cell proliferation and cell survival. YAP1/TAZ-TEAD activity has further been implicated as a mechanism of resistance to targeted therapies. Here, we investigate the effect of combining TEAD inhibitors with KRASG12C inhibitors in KRASG12C mutant NSCLC tumor models. We show that TEAD inhibitors, while being inactive as single agents in KRASG12C-driven NSCLC cells, enhance KRASG12C inhibitor-mediated anti-tumor efficacy in vitro and in vivo. Mechanistically, the dual inhibition of KRASG12C and TEAD results in the downregulation of MYC and E2F signatures and in the alteration of the G2/M checkpoint, converging in an increase in G1 and a decrease in G2/M cell cycle phases. Our data suggest that the co-inhibition of KRASG12C and TEAD leads to a specific dual cell cycle arrest in KRASG12C NSCLC cells.

<p>Supplementary Tables S1. Table S1 describes the inhibitory activity of SAR260301 on AKT phosphorylation (Ser473 and Thr308) in a panel of tumor cell lines with different genetic abnormalities that are reported. Supplementary Figures S1-S4. Figure S1 illustrates the selectivity of SAR260301 against VPS34 in cellular setting: Figure S1A describes the activity of SAR260301 on VPS34 kinase function in GFP-FYVE cellular assay; Figure S1B describes the activity of SAR260301 on autophagy in GFP-LC3 cellular assays. Figure S2 describes the inhibitory activity of SAR260301 on the phosphorylation of AKT downstream effectors PRAS40 and S6RP in PC3 cell line, as a function of time. Figure S3 describes the in vitro antitumor activity of SAR260301: Figure S3A describes the antiproliferative activity of SAR260301on MEF-3T3-myr p110β cells. Figure S3B describes the antiproliferative activity of SAR260301on PC3 cells. Figure S3C describes the activity of SAR260301on PC3 cell death. Figure S3D describes the activity of SAR260301on LnCaP cell apoptosis. Figure S4 is a scheme describing the rationale for combining inhibitors of PI3K� and MAPK.</p>