Abstract B36: Re-activation of protein phosphatase 2A as a multi-target strategy for combating chemotherapy resistance of common cancer types

Abstract

Abstract Either intrinsic or acquired drug resistance is the major problem related to currently used chemotherapies. Traditionally, drug resistance to certain classes of chemotherapies have been linked to altered activity of a particular signaling pathway, or for example enhanced drug efflux activity. Based on these work, novel strategies for chemosensitization has been tested, but usually with rather disappointing results. This is likely to be caused by cancer cells capacity to rapidly adjust to inhibition of single targeted signaling pathway. Therefore, it has been suggested that simultaneous multi-target inhibition would be required for efficient chemosensitization. Protein phosphatase 2A (PP2A) is a trimeric protein phosphatase complex consisting of catalytic C-subunit (PP2Ac), scaffolding A-subunit (PR65) and various regulatory B-subunits. Importantly, it has been estimated that collectively PP2A complexes can dephosphorylate vast majority of all cellular serine/threonine phosphorylated proteins. Importantly, inhibition of PP2A activity is a prerequisite for human cell transformation and thereby, by default, PP2A is inhibited in all human cancer cells (Westermarck and Hahn, 2008). Regarding wide-spectrum role of PP2A on cellular signaling, it has been reasoned that re-activation of inhibited PP2A complexes would result in simultaneous inhibition of multiple oncogenic pathways. Our laboratory recently identified CIP2A as a novel PP2A inhibitor protein (Junttila et al., 2007), and was first to demonstrate cancer-promoting roles for both CIP2A and another PP2A inhibitor protein PME-1 (Junttila et al., 2007; Puustinen et al., 2009). Expression of both of these proteins shows strong association with tumor progression in human patients (Junttila et al., 2007; Khanna et al., 2009; Puustinen et al., 2009). Here we have studied the role of PP2A inhibitor proteins CIP2A and PME-1 in chemotherapy resistance. Small scale screening library of small molecule compounds targeting different parts of the human kinome was used to identify synthetic lethality with either CIP2A or PME-1 depletion in cancer cell lines. Based on initial screen we have now identified a number of derivatives and structural analogues of certain group of kinase inhibitors that are lethal specifically to the CIP2A and PME-1 depleted cancer cells. Importantly, several of these drugs have previously been used in clinical trials. The efficacy of these compounds in combination with CIP2A and PME-1 depletion is demonstrated in many different cancer cell lines in vitro. The in vivo assessment of CIP2A and PME-1 siRNA and treatment with these compounds in xenograft mouse models is in progress. Furthermore, regarding potential side-effect profile of PP2A reactivation, we have examined the consequences of combined CIP2A inhibition and chemotherapy treatment in vivo by using the CIP2A deficient mouse model. Together these results suggest that a potential biological outcome of aberrant PP2A signaling in cancer is conferring drug resistance. Based both on these results, and on wide-spectrum role of PP2A on cellular signaling (Westermarck and Hahn, 2008), we hypothesize that re-activation of PP2A, via targeting of its endogenous inhibitory proteins, could be used as a general strategy for multi-target inhibition of chemoresistance in common human cancer types. In addition, these results may have importance in patient stratification for monotherapies using the identified small molecule compounds.