Abstract LB-217: CK2 protein kinase promotes resistance to MAPK pathway inhibition

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Small molecule kinase inhibitors have opened potential new avenues for treating cancers dependent on the RAS-RAF-MEK-ERK MAPK pathway, yet identification of both de novo/innate/intrinsic and acquired resistance mechanisms will be critical for the successful application of these inhibitors in the clinic. We interrogated the kinome to identify resistance mechanisms towards the novel ERK1/2-selective inhibitor SCH772984. We first utilized a kinome-focused RNAi screen to identify genes that, when silenced, sensitized KRAS-dependent pancreatic cancer cells to SCH772984. In our drug dose-response screen of 711 kinases (QIAGEN library), we used 4 independent siRNA duplexes to knock down each gene, treated at 5 different drug doses, then evaluated viability with a standard CellTiter-Glo assay. Nineteen kinases enhanced sensitivity to SCH772984 (where at least 2 siRNAs for each target decreased IC50) at least 5-fold, indicating that they could drive ERK1/2 inhibitor resistance. Among these were 4 of the 9 protein kinases (Cot, Raf-1, PAK3 and PRKCH) identified in a cDNA expression screen for kinases that caused resistance of BRAF-mutant melanoma to the BRAF inhibitor vemurafenib. We therefore hypothesized that at least some of the kinases that scored positive in this screen might be conserved both across the MAPK pathway and across different cancer types. The tetrameric protein kinase CK2 (formerly casein kinase II) has crucial roles in cell survival, proliferation and differentiation, and its expression and/or activity is dysregulated in cancers including melanoma. In very recent studies, we have now determined that the alpha subunit of CK2 is sufficient to cause resistance to each of the three ERK MAPK pathway inhibitors currently approved for treatment of melanoma: vemurafenib (BRAFi), dabrafenib (BRAFi) and trametinib (MEKi). Co-inhibition of the MAPK pathway and CK2 (e.g., with CX-4945, currently in phase I trials) further enhanced sensitivity. Thus, this combination may offer an effective regimen to forestall or delay tumor relapse. We also observed that CK2alpha maintains ERK phosphorylation in the presence of MAPK inhibitors, and that it posttranslationally reduces abundance of the ERK phosphatase DUSP6/MKP-3, in a kinase-dependent manner. The relationship of these findings to CK2-mediated mechanisms of drug resistance will be discussed. Citation Format: Bingying Zhou, Michelle Kassner, Holly Yin, Channing J. Der, Adrienne D. Cox. CK2 protein kinase promotes resistance to MAPK pathway inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-217. doi:10.1158/1538-7445.AM2014-LB-217