Druggable cancer phosphatases

Abstract

The phosphorylation status of oncoproteins is regulated by both kinases and phosphatases. Kinase inhibitors are rarely sufficient for successful cancer treatment, and phosphatases have been considered undruggable targets for cancer drug development. However, innovative pharmacological approaches for targeting phosphatases have recently emerged. Here, we review progress in the therapeutic targeting of oncogenic Src homology region 2 domain-containing phosphatase-2 (SHP2) and tumor suppressor protein phosphatase 2A (PP2A) and select other druggable oncogenic and tumor suppressor phosphatases. We describe the modes of action for currently available small molecules that target phosphatases, their use in drug combinations, and advances in clinical development toward future cancer therapies.

CIP2A Interacts with TopBP1 and Drives Basal-Like Breast Cancer Tumorigenesis

“…In addition to identifying CIP2A as a driver candidate for BLBC, we demonstrate that SMAPs ( 14) function as transcriptional inhibitors of CIP2A expression. Our results reveal a model where SMAPs initially directly activate PP2A-B56 (14,16), and this followed by a prolonged PP2A activation due to transcriptional downregulation of CIP2A. Importantly, we were also able to demonstrate that CIP2A overexpression rescued the effects of SMAPs as assessed by both decreases in cell viability and H2AX regulation.…”

“…CIP2A also promotes pro-proliferative MYC and E2F1 activities in BLBC cells. Finally, we discover that small molecules shown previously to activate PP2A (16,22), transcriptionally inhibit CIP2A expression, and serve as candidate therapeutics for CIP2A-positive BLBCs.…”

“…3C and S3B), as well as towards MYC and E2F1 (Fig. 5J), we tested whether a recently developed series of Small Molecule Activators of PP2A (SMAPs) (14,16), could be used to target CIP2A-expressing BLBC. SMAPs activate the CIP2A-regulated PP2A-B56alpha heterotrimer (14,44), and the cellular effects of SMAPs in cancer cells are both correlated with PP2A reactivation capacity, and can be rescued by concomitant PP2A inhibition (22,45).…”

“…Recently the serine/threonine phosphatase PP2A has gained attention as a druggable tumor suppressor (14)(15)(16). Of specific relevance to this work, is the role of serine/threonine phosphatases in the DNA damage response at chromatin (6), which could link them to cancer types with homologous recombination defects, and high mutational burden, such as BLBCs.…”

“…However, it is currently unclear what role CIP2A plays in BLBC initiation, or progression. Notably, understanding of CIP2A-related cancer initiation mechanisms is also therapeutically relevant due to the recent development of small molecule activators of the CIP2A-inhibited PP2A-B56 heterotrimer that demonstrate potent antitumor activities (14,16).…”