Abstract PR03: Targeting CREB-CBP transcription factor complex using small molecule inhibitors with multifunctional anticancer mechanisms.

Abstract

Abstract Lung cancer is the most common form of cancer in the world and the leading cause of cancer-related deaths in both men and women in the United States. It is estimated that 159,480 lung cancer patients will die in United States in 2013. Approximately 25% of lung adenocarcinomas harbor oncogenic KRAS mutations, and this poses a significant therapeutic challenge, as KRAS mutations are generally associated with poor prognosis and resistance to chemotherapy. There is an unmet therapeutic need for patients with KRAS mutated tumors. Direct pharmacologic targeting of activated KRAS mutant protein has been unsuccessful so far, therefore, other approaches to abrogate KRAS signaling other than through direct inhibition, are being considered. One option to inhibit growth of KRAS mutant tumors may be to target transcription factors, which are often the final regulator of multiple signaling processes, and could potentially be targeted regardless of alterations of upstream signaling components involved in cancer development, progression and invasion/metastasis. CREB is a transcription factors that binds to the specific DNA sequence 5'-TGACGTCA-3', which is known as CRE, in the transcription-regulatory regions of many cAMP-regulated genes with cell-type specificity. Studies have shown that CREB is activated via diverse signaling pathways, including Ras-ERK1/2, PI-3K-Akt, and mTOR signaling pathway. Numerous kinases in these pathways are known to activate CREB in response to a variety of extracellular stimuli (i.e., growth factors, stress signals) and intracellular oncogenic activation mutations. Virtually, almost all of the signaling pathways playing critical roles in carcinogenesis/tumorigenesis are shown to activate CREB. Upon activation, CREB recruit transcriptional coactivator CREBBP (CBP) and directly regulates multiple genes involved in cancer pathogenesis. We previously demonstrated that CREB is a critical transcription factor lung cancer development through its involvement in cell survival, cell cycle progression, proliferation and apoptosis regulation. We, then, first proposed that CREB could be a molecular target for the prevention and treatment of NSCLC. We demonstrated that blocking CREB activity or expression in cancer cells resulted in the suppression of growth and proliferation and induction of cell death. We also reported that CREB regulates expression of pro-inflammatory, pro-angiogenic, and pro-metastatic CXC type chemokine genes and that an inhibitor of CREB blocked the expression and pro-tumorigenic activity of these chemokines. Furthermore, we showed that CREB is highly upregulated and hyperphosphorylated in most of the NSCLC tumor specimens and that this upregulation is significantly associated with poor survival rates as determined in more than 300 cases of NSCLC patients. Thus, these studies lead to the rationale for identification of small molecule inhibitors targeting CREB transcriptional activity described in this study. Here, we will discuss our recent findings that novel small-molecule inhibitors (SMI) targeting the CREB-CBP transcription factors complex are effective in suppression of growth and proliferation of several lung cancer cell lines with various oncogenic mutations, such as KRas-G12D, -G12C, -G12V, or -G12S, and even EGFR-T790M. Furthermore, the small molecule regressed tumors in the KrasG12D/+;p53-/- preclinical mouse lung cancer model. Interestingly, the SMIs also showed similar growth suppressive effect on some pancreatic cancer cell lines and breast cancer cell lines. We found that the SMIs have multifunctional anti-cancer effects including cell cycle arrest, suppression of tumor-promoting autophagy, induction of ER stress, and ultimately cell death. Our results strongly suggest that these novel molecules targeting CREB-CBP transcription factor complex may have potential therapeutic benefit, particularly, cancers harboring various oncogenic mutations, including KRAS and EGFR mutations. This abstract is also presented as Poster B04. Citation Format: Jong Woo Lee, Hee Sun Park, Sin-aye Park, Roy S. Herbst, Jaseok Peter Koo. Targeting CREB-CBP transcription factor complex using small molecule inhibitors with multifunctional anticancer mechanisms. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr PR03.