This differential sensitivity may be dependent on a unique molecular signature. The signature of responders to RO4929097 will emerge as clinical data accumulate from ongoing trials with this compound in melanoma, and will help to define the subset of patients that will benefit the most from RO4929097 treatment. These studies may also help to conceive combinatorial treatments of RO4929097, which, even when effective, does not cause a profound inhibition of tumor growth, but is able to affect tumor initiating ability, with other drugs that, conversely, are more effective at preventing tumor growth, but fail to decrease the tumor initiating ability. Alternatively, RO4929097 could also be effective in the adjuvant setting to prevent metastatic spread. In summary, our preclinical studies support the gamma secretase inhibition as a novel approach that is able to target the melanoma initiating pool and offer insights into the clinical potential of this new treatment strategy. The most highly conserved domain of the ING proteins is their plant homeodomain, a form of zinc DAPT finger. PHDs in INGs interact with core histone proteins in a histone methylation-sensitive manner, implicating ING proteins as interpreters of the histone epigenetic code. This mechanism is well-conserved considering that progressive methylation of yeast histone H3K4 also increases ING histone affinity. ING2 directs the acetylation of histone H3-residue K14, suggesting that INGs regulate the histone code by linking histone methylation to -acetylation. Additionally, the polybasic region adjacent to the ING2-PHD is necessary and sufficient for binding stress-inducible phosphoinositide signaling lipids that activate ING2 to promote apoptosis. Of all ING proteins, ING2 shares highest sequence-homology and most functional similarities with ING1. ING1 and ING2 enhance acetylation of p53 on lysine-residues that are linked to p53-activation and inactivated by hSir2. Binding of ING1 to p53 was reported to be required for p53activity and may prevent binding of the MDM2 ubiquitin E3ligase to p53, thereby preventing proteasomal degradation of p53. However, ING1 also induces apoptosis independently of p53. Hence, whether significant interactions between endogenous p53 and ING1 occur in vivo requires clarification. The ubiquitin-proteasome pathway regulates levels, activity and location of about 80% of growth-regulatory proteins and transcription factors with short half-lives, such as cyclins, p21WAF1 and p53, through a network of ubiquitin-transferring proteins, ubiquitin E2 and E3-ligases, and proteins regulating their activity. Most commonly, proteins are polyubiquitinated, targeting them for rapid degradation by the 26S-proteasome, while monoubiquitination and multi-monoubiquitination have been implicated in cellular stress responses, in chromatin remodeling and in regulating p53-stability. Alterations in ubiquitination are Rapamycin frequent in cancer cells. Various studies on proteasome-inhibitors in cancer treatment already show promising results, but it currently remains unclear, why blocking “non-specific” proteasomal degradation induces differential killing of tumor cells. However, induction of p53-dependent apoptosis is involved in the selective killing of tumor cells by certain proteasome-inhibitors. Therefore, identifying mechanisms that shield p53 from proteasomal degradation might contribute to optimized cancer treatment based on selectively targeting the ubiquitin-proteasome-machinery.