Targeting CREB in Cancer Therapy: A Key Candidate or One of Many? An Update

SIMPLE SUMMARY: Only 5% of all drug-related targets currently move from preclinical to clinical in cancer, and just some of them achieve patient’s bedside. Among others, intratumor heterogeneity and preclinical cancer model limitations actually represent the main reasons for this failure. Cyclic-AMP response element-binding protein (CREB) has been defined as a proto-oncogene in different tumor types, being involved in maintenance and progression. Due to its relevance in tumor pathophysiology, many CREB inhibitor compounds have been developed and tested over the years. Herein, we examine the current state-of-the-art of both CREB and CREB inhibitors in cancer, retracing some of the most significant findings of the last years. While the scientific statement confers on CREB a proactive role in cancer, its therapeutic potential is still stuck at laboratory bench. Therefore, pursuing every concrete result to achieve CREB inhibition in clinical might give chance and future to cancer patients worldwide. ABSTRACT: Intratumor heterogeneity (ITH) is considered the major disorienting factor in cancer treatment. As a result of stochastic genetic and epigenetic alterations, the appearance of a branched evolutionary shape confers tumor plasticity, causing relapse and unfavorable clinical prognosis. The growing evidence in cancer discovery presents to us “the great paradox” consisting of countless potential targets constantly discovered and a small number of candidates being effective in human patients. Among these, cyclic-AMP response element-binding protein (CREB) has been proposed as proto-oncogene supporting tumor initiation, progression and metastasis. Overexpression and hyperactivation of CREB are frequently observed in cancer, whereas genetic and pharmacological CREB downregulation affects proliferation and apoptosis. Notably, the present review is designed to investigate the feasibility of targeting CREB in cancer therapy. In particular, starting with the latest CREB evidence in cancer pathophysiology, we evaluate the advancement state of CREB inhibitor design, including the histone lysine demethylases JMJD3/UTX inhibitor GSKJ4 that we newly identified as a promising CREB modulator in leukemia cells. Moreover, an accurate analysis of strengths and weaknesses is also conducted to figure out whether CREB can actually represent a therapeutic candidate or just one of the innumerable preclinical cancer targets.