A combined opposite targeting of p110δ PI3K and RhoA abrogates skin cancer.

Malignant melanoma is the most aggressive and deadly skin cancer with an increasing incidence worldwide whereas SCC is the second most common non-melanoma human skin cancer with limited treatment options. Here we show that the development and metastasis of melanoma and SCC cancers can be blocked by a combined opposite targeting of RhoA and p110δ PI3K. We found that a targeted induction of RhoA activity into tumours by deletion of p190RhoGAP-a potent inhibitor of RhoA GTPase-in tumour cells together with adoptive macrophages transfer from δD910A/D910A mice in mice bearing tumours with active RhoA abrogated growth progression of melanoma and SCC tumours. Τhe efficacy of this combined treatment is the same in tumours lacking activating mutations in BRAF and in tumours harbouring the most frequent BRAF(V600E) mutation. Furthermore, the efficiency of this combined treatment is associated with decreased ATX expression in tumour cells and tumour stroma bypassing a positive feedback expression of ATX induced by direct ATX pharmacological inactivation. Together, our findings highlight the importance of targeting cancer cells and macrophages for skin cancer therapy, emerge a reverse link between ATX and RhoA and illustrate the benefit of p110δ PI3K inhibition as a combinatorial regimen for the treatment of skin cancers.

p110δ PI3K as a therapeutic target of solid tumours.

From the time of first characterization of PI3K as a heterodimer made up of a p110 catalytic subunit and a regulatory subunit, a wealth of evidence have placed the class IA PI3Ks at the forefront of drug development for the treatment of various diseases including cancer. The p110α isoform was quickly brought at the centre of attention in the field of cancer research by the discovery of cancer-specific gain-of-function mutations in PIK3CA gene in a range of human solid tumours. In contrast, p110δ PI3K was placed into the spotlight of immunity, inflammation and haematologic malignancies because of the preferential expression of this isoform in leucocytes and the rare mutations in PIK3CD gene. The last decade, however, several studies have provided evidence showing that the correlation between the PIK3CA mutations and the response to PI3K inhibition is less clear than originally considered, whereas concurrently an unexpected role of p110δ PI3K in solid tumours has being emerging. While PIK3CD is mostly non-mutated in cancer, the expression levels of p110δ protein seem to act as an intrinsic cancer-causing driver in various solid tumours including breast, prostate, colorectal and liver cancer, Merkel-Cell carcinoma, glioblastoma and neurobalstoma. Furthermore, p110δ selective inhibitors are being studied as potential single agent treatments or as combination partners in attempt to improve cancer immunotherapy, with both strategies to shown great promise for the treatment of several solid tumours. In this review, we discuss the evidence implicating the p110δ PI3K in human solid tumours, their impact on the current state of the field and the potential of using p110δ-selective inhibitors as monotherapy or combined therapy in different cancer contexts.