Abstract Metastatic non-small cell lung cancer (NSCLC) is the most common cause of cancer death. Cytotoxic chemotherapy has historically been the mainstay of therapy but is associated with only modest improvements in patient survival. Over the past decade, a better understanding of the pathogenesis of NSCLC, coupled with high throughput genomic technologies applied to patient tumor samples, has led to a molecular classification of NSCLC and a new generation of “precision” therapies. However, the most common recurrent oncogenomic mutation driving the growth of NSCLC, mutant KRAS, accounting for ∼25% of patients with advanced NSCLC, remains without an effective targeted therapy. Mutations in KRAS lead to downstream signaling through ERK, as well as cross talk with the PI3K-Akt pathway, the latter of which is amplified in the presence of inhibition of ERK pathway signaling alone. These findings likely explain, at least in part, why targeting ERK pathway signaling alone in NSCLC has been largely unsuccessful in the clinic, and suggest that coordinate inhibition of both ERK and Akt is necessary for optimal therapy. Approaches to inhibit both of these pathways simultaneously with co-administration of two small molecular kinase inhibitors has shown some promise, but has been limited by both “off-target” treatment-limiting side effects and suboptimal coordinate inhibition of both Akt and ERK signaling. Thus, novel therapies, are critically needed, to improve the lives of patients suffering from KRAS driven lung cancers and while oncogenic kinases have proven to be successful targets for cancer treatment, the therapeutic targeting of phosphatases, the key negative regulators of these same pathways, has remained largely unexplored. Starting with the observation that tricyclic neuroleptic drugs exert anticancer effects in xenograft models, we employed combinatorial chemistry to reverse engineer these drugs into a series of novel compounds that retain the anti-proliferative effects but are devoid of the dose-limiting effects on the central nervous system. We have demonstrated these agents exert potent anti-proliferative effects in both cell culture and in vivo lung cancer models and these effects are functionally linked with simultaneous inhibition of both PI3K-Akt and MAPK signaling. Importantly, these agents that have favorable pharmaceutic properties directly bind and activate the serine/threonine phosphatase 2A (PP2A) and we call these novel first-in-class agents Small Molecule Activators of PP2A (SMAPs). A critical role for PP2A as a tumor suppressor has previously been established, and inhibition and loss-of-function changes in PP2A occur in human lung cancers. Furthermore, protein phosphatase 2A (PP2A) accounts for the majority of cellular serine/threonine phosphatase activity, and its dominant and best defined targets are protein kinases and oncogenic proteins including ERK and AKT. Here we demonstrate for the first time the development and validation of a first-in-class orally bioavailable pharmacological agent that can directly bind and activate PP2A driving coordinate inhibition of both the MAPK and AKT effector pathways in cell culture and both xenograft and genetically engineered mouse models (GEMM) of human lung cancer. Global phosphoproteomic analysis of SMAP treated KRAS lung cancer cell lines reveals ERK signaling as the only commonly perturbed pathway in drug treated cell lines. Single agent SMAP treatment of KRAS GEMM and xenograft mouse models of lung cancer resulted in tumor stasis, induction of tumor cell apoptosis and cell cycle arrest to comparable levels seen with a combination of AKT and MEK inhibitors. Additionally, the compounds demonstrate favorable pharmacokinetics and show no overt toxicity. Taken together, these findings point to therapeutic activation of PP2A as a novel strategy for the treatment of advanced KRAS-mutant NSCLC. While research and clinical effort has largely focused on development of inhibitors of oncogenic kinases, the identification of small molecule activators of tumor suppressor proteins has remained elusive. Activation of such proteins could offer the opportunity to identify novel synergistic strategies for the treatment of a number of cancer types. Nevertheless, translation of a PP2A activation strategy into clinical medicine has required pharmaceutically tractable agents for development. Our studies represent a first step into that new territory and highlight the potential for the development of small molecule activators of other protein phosphatases and tumor suppressor proteins. Citation Format: Jaya Sangodkar, Sahar Mazhar, Danica Wiredja, Giridharan Gokulrangan, Daniela Schlatzer, David Kastrinsky, Analisa Difeo, Shen Yao, Sudeh Izadmehr, Neelesh Sharma, Yiannis Ioannou, Michael Ohlmeyer, Goutham Narla. Therapeutic targeting of oncogenic KRAS signaling using a novel small molecule agonist of the PP2A tumor suppressor gene. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A38. doi: 10.1158/1557-3125.RASONC14-A38
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Mar 13, 2024
Jialin Mo + 20
