Protein phosphatase 2A (PP2A) comprises a family of serine/threonine phosphatases, minimally containing a well-conserved catalytic subunit. PP2A plays a prominent role in the regulation of specific signal transduction cascades. Additionally, PP2A interacts with a substantial number of other cellular and viral proteins. DT-061 is an orally bioavailable small-molecule activator of PP2A.
In this study, researchers characterized protein phosphatase 2A (PP2A) activity as a global determinant of KRAS-mutant lung cancer cell resistance across a library of >200 kinase inhibitors. PP2A activity modulation alters cancer cell sensitivities to a large number of kinase inhibitors. Specifically, PP2A inhibition ablated MEK inhibitor response through the collateral activation of AKT/mammalian target of rapamycin (mTOR) signaling. The combination of mTOR and MEK inhibitors induced cytotoxicity in PP2A-inhibited cells, but even this drug combination could not abrogate MYC up-regulation in PP2Ainhibited cells.
Treatment with DT-061 in combination with the MEK inhibitor AZD6244 results in suppression of both p-AKT and MYC. The combination therapy also makes tumor regression in two KRAS-driven lung cancer mouse models. DT-061 therapy also abrogates MYC-driven tumorigenesis. PP2A deregulation drives MEK inhibitor resistance in KRAS-mutant cells. DT-061 shows dose-dependent inhibition of colony growth as single agents in KRAS-mutant H441 and H358 cell lines. DT-061 treatment induces a dose-dependent caspase-3/7 activation.
Both DT-061 and AZD6244 show single-agent activity, but their combination was significantly more efficient than either of the compounds alone, assessed by inhibition of the tumor volume. DT-061 treatment induces a dose-dependent caspase-3/7 activation. PP2A inhibition is a druggable MEK inhibitor resistance mechanism in KRAS-mutant lung cancer cells.
All in all, PP2A inhibition is a druggable MEK inhibitor resistance mechanism in KRAS-mutant lung cancer cells.