Further, we have integrated the conventional role of PTEN as a master regulator of PIP3 levels and proposed a novel concept in favour of a PIP3-independent role of the PTEN catalytic functions in response to therapies and beyond, and hope that through future studies these, as well as additional theories and hypotheses, will lead us to a better and more comprehensive understanding of the PI3K signaling network towards effective combinatorial treatments for cancer. The gene discussed is PIK3CA; the disease is cancer.