PNNL

Abstract

Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft tissue sarcomas with limited treatment options, and novel effective therapeutic strategies are desperately needed. We have reported the activity of combined inhibition of MEK and SHP2 in MPNST as a strategy to overcome inhibitor-induced activation of upstream receptor tyrosine kinases and to deepen responses, but this strategy may be limited by both overlapping toxicity and prior exposure to MEK inhibitor as treatment for precursor plexiform neurofibroma. We therefore now focus on SHP2-based strategies and observe anti-proliferative efficacy of both genetic depletion and pharmacological inhibition using the clinically available SHP2 inhibitor (SHP2i) TNO155. Our studies into the key features of the signaling response to SHP2i reveal that resistance to TNO155 is partially mediated by reduced RB function, and we therefore test the addition of a CDK4/6 inhibitor (CDK4/6i) to enhance RB function and improve TNO155 efficacy. In combination, TNO155 attenuates the adaptive response to CDK4/6i, potentiates its anti-proliferative effects, and converges on enhancement of RB activity, with greater suppression of cell cycle and inhibitor-of- apoptosis proteins, leading to deeper and more durable anti-tumor activity in both in vitro and in vivo patient-derived models of MPNST, relative to either single agent. These data suggest that SHP2i plus CDK4/6i is a potent combination of RAS signaling pathway inhibitors and demonstrates profound anti-tumor efficacy and is well-tolerated. Overall, our study provides timely evidence to support the clinical advancement of this combination strategy in patients with MPNST and other tumors driven by loss of NF1.