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

Abstract

Malignant peripheral nerve sheath tumors often arise in patients with neurofibromatosis type 1 and are among the most treatmentrefractory types of sarcoma. Overall survival in patients with relapsed disease remains poor, and thus novel therapeutic approaches are needed. NF1 is essential for negative regulation of RAS activity and is altered in about 90% of malignant peripheral nerve sheath tumors (MPNST). A complex interplay of upstream signaling and parallel RAS-driven pathways characterizes NF1driven tumorigenesis, and inhibiting more than one RAS effector pathway is therefore necessary. To devise potential combination therapeutic strategies, we identified actionable alterations in signaling that underlie adaptive and acquired resistance to MEK inhibitor (MEKi). Using a series of proteomic, biochemical, and genetic approaches in an in vitro model of MEKi resistance provided a rationale for combination therapies. HGF/MET signaling was elevated in the MEKi-resistant model. HGF overexpression conferred resistance to MEKi in parental cells. Depletion of HGF or MET restored sensitivity of MEKi-resistant cells to MEKi. Finally, a combination of MEK and MET inhibition demonstrated activity in models of MPNST and may therefore be effective in patients with MPNST harboring genetic alterations in NF1.Significance: This study demonstrates that MEKi plus MET inhibitor may delay or prevent a novel mechanism of acquired MEKi resistance, with clinical implications for MPNST patients harboring NF1 alterations.

Preclinical Assessment of MEK Inhibitors for Malignant Peripheral Nerve Sheath Tumors Reveals Differences in Efficacy and Adaptive Response

“…A similar variation tendency in cyclin D1 expression was observed. As demonstrated in previous studies, MEK inhibition could reactivate MAPK signaling or upregulate parallel signaling pathways, particularly, the PI3K pathway, resulting in reduced efficacy of MEK inhibitors ( 27 ). It was also observed in S462 cells that compensatory increases in p-MEK and p-AKT occurred after 24 h of MEK inhibitor treatment.…”

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

“…Although the landmark trials only include inoperable patients, anecdotal reports suggest that MEK inhibitors could have a role. 59 However, although most of the patients do respond, tumor shrinkage is modest (15%-30%). Combination strategies might overcome resistance to monotherapy 56 , 57 and offer additional volumetric tumor shrinkage to further optimize surgery, but this is still an underexplored field of research in NF1-related PNs.…”

SHP2 Inhibition as a Promising Anti-cancer Therapy: Function in Tumor Cell Signaling and Immune Modulation

“…SHP2 inhibition enhances the efficacy of tyrosine kinase inhibitors (TKI), such as ALK/EGFR/FGFR inhibitors, in drug-resistant NSCLC and metastatic breast cancer, in which distinct RTK activation mediates adaptive and acquired resistance [25][26][27][28]. In addition, SHP2 inhibition (or depletion) also restores sensitivity to ERK signaling inhibition and has additive/synergistic anti-tumor effects when combined with KRAS G12C /RAF/MEK inhibitors in multiple models of cancers driven by hyperactivated RAS, including KRASmutant pancreatic, lung and colorectal cancers, KRAS WTamplified gastroesophageal cancer, RAS WT triple negative breast cancer (TNBC) and ovarian cancers, NRAS-mutant neuroblastoma, NF1-deficient MPNST, and BRAF-mutant colon and thyroid cancers, among others, through blocking signal transduction from most RTK that are reactivated through loss of negative feedback following ERK pathway inhibition [19,24,26,[29][30][31][32][33][34][35][36][37][38].…”

“…MEKi alone, however, has limited anti-tumor activity, leading to the notion that combinations that target the adaptively upregulated molecules that emerge upon loss of ERK-induced negative feedback should be effective. Our data suggested that a number of tyrosine and serine/threonine kinases become adaptively upregulated in response to MEKi, leading to challenges in the design of MEKi plus TKI combination strategies, as genomic or other predictive biomarkers to identify the adaptively changed RTK are not readily discernible [24,32]. In order to overcome this challenge, we posited that inhibition of the central node of convergence between the RTK and RAS recruitment to the membrane and activation -SHP2 -would serve as a viable strategy.…”