CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon RB function in malignant peripheral nerve sheath tumors
Menée à l'aide de lignées cellulaires et de xénogreffes de tumeurs malignes des gaines des nerfs périphériques avec déficience de la neurofibromine NF1, cette étude met en évidence un mécanisme par lequel l'inhibition des kinases CDK4/6 accroît l'efficacité antitumorale des inhibiteurs de phosphatase SHP-2 via l'augmentation de l'activité de la protéine RB
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas with limited treatment options, and new effective therapeutic strategies are desperately needed. We observe antiproliferative potency of genetic depletion of PTPN11 or pharmacological inhibition using the SHP2 inhibitor (SHP2i) TNO155. Our studies into 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 activity and improve TNO155 efficacy. In combination, TNO155 attenuates the adaptive response to CDK4/6i, potentiates its antiproliferative 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 antitumor activity in in vitro and in vivo patient-derived models of MPNST, relative to either single agent. 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. SHP2i and CDK4/6i provide antitumor efficacy through enhancing RB function in patient-derived models of NF1-deficient MPNST.