SHP2 inhibition displays efficacy as a monotherapy and in combination with JAK2 inhibition in preclinical models of myeloproliferative neoplasms

Abstract

Myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocytosis, and primary myelofibrosis, are clonal hematopoietic neoplasms driven by mutationally activated signaling by the JAK2 tyrosine kinase. Although JAK2 inhibitors can improve MPN patients' quality of life, they do not induce complete remission as disease‐driving cells persistently survive therapy. ERK activation has been highlighted as contributing to JAK2 inhibitor persistent cell survival. As ERK is a component of signaling by activated RAS proteins and by JAK2 activation, we sought to inhibit RAS activation to enhance responses to JAK2 inhibition in preclinical MPN models. We found the SHP2 inhibitor RMC‐4550 significantly enhanced growth inhibition of MPN cell lines in combination with the JAK2 inhibitor ruxolitinib, effectively preventing ruxolitinib persistent growth, and the growth and viability of established ruxolitinib persistent cells remained sensitive to SHP2 inhibition. Both SHP2 and JAK2 inhibition diminished cellular RAS‐GTP levels, and their concomitant inhibition enhanced ERK inactivation and increased apoptosis. Inhibition of SHP2 inhibited the neoplastic growth of MPN patient hematopoietic progenitor cells and exhibited synergy with ruxolitinib. RMC‐4550 antagonized MPN phenotypes and increased survival of an MPN mouse model driven by MPL‐W515L. The combination of RMC‐4550 and ruxolitinib, which was safe and tolerated in healthy mice, further inhibited disease compared to ruxolitinib monotherapy, including extending survival. Given SHP2 inhibitors are undergoing clinical evaluation in patients with solid tumors, our preclinical findings suggest that SHP2 is a candidate therapeutic target with potential for rapid translation to clinical assessment to improve current targeted therapies for MPN patients.

WWP1 inhibition increases SHP2 inhibitor efficacy in colorectal cancer

“…Multiple genes of the RAS/ERK pathway and parallel pathways were found to be involved in SHP2 inhibitor resistance by a genome wide CRISPR/Cas9 screen, including NF1, PTEN, CDKN1B, LZTR1, and RASA2 36 . Both the SHP2 inhibitor RMC4550 and the JAK2 inhibitor decreased RAS-GTP levels in myeloproliferative neoplasm cells, and their combined employment enhanced ERK inactivation and increased apoptosis 37 . CDK4/6 inhibitor increased the efficacy of SHP2 inhibitor TNO155 by enhancing RB activity, greater inhibited cell cycle and apoptosis inhibitory proteins, which resulted in deeper and more sustained anti-tumor activity in malignant peripheral nerve sheath tumor models 38 .…”