Combined Inhibition of SHP2 and MEK Is Effective in Models of NF1-Deficient Malignant Peripheral Nerve Sheath Tumors

Abstract

◥Loss of the RAS GTPase-activating protein (RAS-GAP) NF1 drives aberrant activation of RAS/MEK/ERK signaling and other effector pathways in the majority of malignant peripheral nerve sheath tumors (MPNST). These dysregulated pathways represent potential targets for therapeutic intervention. However, studies of novel single agents including MEK inhibitors (MEKi) have demonstrated limited efficacy both preclinically and clinically, with little advancement in overall patient survival. By interrogation of kinome activity through an unbiased screen and targeted evaluation of the signaling response to MEK inhibition, we have identified global activation of upstream receptor tyrosine kinases (RTK) that converges on activation of RAS as a mechanism to limit sensitivity to MEK inhibition. As no direct inhibitors of pan-RAS were available, an inhibitor of the protein tyrosine phosphatase SHP2, a critical mediator of RAS signal transduction downstream of multiple RTK, represented an alternate strategy. The combination of MEKi plus SHP099 was superior to MEKi alone in models of NF1-MPNST, including those with acquired resistance to MEKi. Our findings have immediate translational implications and may inform future clinical trials for patients with MPNST harboring alterations in NF1.Significance: Combined inhibition of MEK and SHP2 is effective in models of NF1-MPNST, both those na€ ve to and those resistant to MEKi, as well as in the MPNST precursor lesion plexiform neurofibroma.

Activation of Receptor Tyrosine Kinases Mediates Acquired Resistance to MEK Inhibition in Malignant Peripheral Nerve Sheath Tumors

“…S1). These findings were consistent with the global upregulation of multiple RTK detected using the PamChip phosphopeptide array in a subset of these cell lines at 24 hours of trametinib treatment relative to control (30). Further, total PDGFRb protein expression was induced by trametinib at 24hour time point in the nine cell lines tested, and this effect was durable in several cell lines, including STS26T, NF94.3, and NF10.1 (Fig.…”

“…We identified a broad variety of RTK that characterize the adaptive response to MEK inhibition in MPNST. One strategy to overcome the pan-RTK upregulation is to target a convergence point vulnerability of RTK/RAS activity-a small-molecule inhibitor of the SHP2 phosphatase together with a MEK inhibitor, indeed, produces synergistic inhibition of NF1-MPNST models in vitro and in vivo (30). SHP2 inhibitors are currently available only through select clinical trials, however, and their tolerability and toxicity in humans, alone or in combination with MEK inhibitors, are not yet reported.…”

Novel molecular targeted therapies for patients with neurofibromatosis type 1 with inoperable plexiform neurofibromas: a comprehensive review

“…Although the safety profile of MEK inhibitors seems to be acceptable, AEs can decrease treatment compliance and affect the QoL. 58 Skin toxicity, asymptomatic increase in creatine kinase, and gastrointestinal symptoms are the most frequent AEs. In the SPRINT trial, 28% of the patients required dose reduction, and 10% discontinued therapy due to DLT.…”

Ex vivo to in vivo model of malignant peripheral nerve sheath tumors for precision oncology

“…Engraftment success was defined as the ability of the PDX line to be serially transplanted for six passages. JH-2-055-b represents the same line previously published as JH-2-055, but multiple samples have been processed from a single patient, and therefore JH-2-055-b has been renamed accordingly (Wang et al , 2020).…”