The use of protein phosphatase 2A activators in combination therapies for pancreas cancer

Abstract

Pancreatic adenocarcinoma (PDA) is extremely aggressive, often discovered late in disease progression, and associated with extremely high mortality rates. While targeted therapies have shown great promise in cancers such as breast and chronic myeloid leukemia, these agents have shown little efficacy in PDA patients. The underlying reasons for this therapeutic resistance is highly debated in the field. From a therapeutic standpoint, the primary target for PDA tumors is oncogenic KRAS, which is almost universally mutated in PDA patients, but considered to be “undruggable.” Additionally, several reports indicate that mutant KRAS makes PDA cells excellent metabolic scavengers, suppresses immune surveillance, and results in a high degree of signaling plasticity that can circumvent single agent treatment [1-3]. Many researchers are now advocating for combination strategies as a means to prevent signaling adaptation and increase therapeutic efficacy in PDA patients. Several therapeutic agents show synergistic activity in combination either with other targeted agents, checkpoint inhibitors, or chemotherapies, highlighting the potential of these strategies for the treatment of this therapeutically refractory disease [4]. Protein phosphatase 2A (PP2A), a major serine/ threonine phosphatase, is a critical regulator of transformation, decreasing the activation of proteins downstream of oncogenic KRAS, including ERK and mTOR. PP2A is aberrantly deactivated in cancer cells, indicating that PP2A suppression may be a common event in cancer progression. Recent work from Kauko et. al. suggests that PP2A regulates an extensive number of cancer related pathways and that the loss of PP2A results in increased therapeutic resistance to over 200 compounds [5]. Conversely, the inhibition of SET, an endogenous PP2A inhibitor, increased the overall therapeutic sensitivity of cells to targeted agents, placing PP2A as a central mediator of therapeutic response. Consistent with the role of PP2A suppression in cancer, therapeutic agents that increase the activity of PP2A have shown excellent anti-tumor responses in pancreas, breast, ovarian, prostate, and lung cancer. Importantly, these agents induce death specifically in cancer cells, with little to no in vivo toxicity, uncovering a cancer cell signaling dependency on PP2A inhibition [6]. Recently, we reported that PP2A activating agents could function synergistically with kinase inhibitors to induce cell death in PDA cells [7]. Similar to SET knockdown, the activation of PP2A reduced the IC50 of multiple therapeutic agents within a kinase inhibitor screen, with inhibitors to EGFR/HER2, Aurora kinases, Src family kinases, and PI3K/mTOR displaying the strongest synergy. Direct PP2A activation, through the use of a Small Molecule Activator of PP2A (SMAP), Editorial