Abstract B24: Targeting ERK-MYC axis in pancreatic cancer

Abstract

Abstract Pancreatic cancer (PCa) is a devastating malignancy with almost 90% lethality of all stages. In PCa, constitutively activated mutated KRAS induces persistent ERK signaling which stabilizes the oncogenic MYC protein. With very limited efficacy of chemotherapy, novel treatment options are urgently need for PCa. Here, we used patient-derived PCa cells and matched PCa tissue explants (PDX) to search for cytotoxic anti-PCa activity among the existing 867 drugs. Only a minority of tested agents were confirmed as active in vivo on patient-matched PDX models. From a short list of the agents with activity in vivo, we focused on triptolide (TLD), an irreversible inhibitor of ERCC3. In pilot testing of triptolide efficacy in a “xenopatient” trial of 8 PCa PDX models, we found that TLD was highly effective against a minority of tumors which achieved complete regression lasting for 3-6 weeks, while other models only showed growth delay. Genomic profiling of highly sensitive PDX models unfirmly demonstrated MYC-amplification. We tested TLD activity in vitro using PDX-matched patient-derived PCa cell lines. Nanomolar TLD elicited rapid (1-4 hours) and profound depletion of MYC oncoprotein in MYC-amplified PCa cell lines, but in PCa cells with normal MYC gene copy number. Furthermore, TLD-resistant PCa cells and PDX tumors exhibited rapid increase of phosphorylated ERK and its downstream targets including stable phospho-MYC protein. This activity of TLD against non-phosphorylated forms of MYC protein suggests interdependence of ERCC3 and MYC in cancer. Expression of ERCC3 was MYC-dependent in a Tet-OFF MYC cell line model. Conversely, silencing of ERCC3 suppressed MYC level. The KRAS->ERK pathway is critical for initiation and progression of PCa. Attempts to disrupt this signaling axis by blocking MEK activity produces only transient cytostatic effect followed by rapid reactivation of the pathway mediated by MYC. Our results further confirm this dependency of PCa on the integrity of the activated KRAS->ERK->MYC signaling axis, and that pharmacological blockade of ERCC3 can be a highly effective strategy against PCa, and in other recalcitrant carcinomas with MYC-amplification. We thus provide a useful biomarker for future clinical development of TLD analogs such as Minnelide which is currently being tested in a Phase I clinical trial. Citation Format: Natalia Beglyarova, Eugenia Banina, Natalya Skobeleva, Vladimir Khazak, Igor Astsaturov. Targeting ERK-MYC axis in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B24.