In addition to inactivation of the p53 and Rb1 pathways, OIS in melanoma and other cancers can be bypassed via activation of PI3K signaling, most frequently via inactivation of PTEN (Dankort et al. 2009; Vredeveld et al. 2012; Conde-Perez et al. 2015). This evidence concerns the gene RB1 and cancer.