PRC2 loss through mutation of its obligate members
SUZ12 or
EED is common and provides a rationale for targeted combination therapies of NF1-associated tumors with bromodomain inhibitors [
54,
58,
59]. The bromodomain protein BRD4 plays a crucial role in NF1-associated MPNST development and comprises a therapeutic target to potentially overcome MEKi resistance [
60]. Interestingly, MPNSTs depleted of BRD4 protein exhibit a strong cytotoxic response to the pan-BET bromodomain inhibitor JQ1 [
61]. Additionally, suppressing
SUZ12 enhances the impact of PD-901/JQ1 administration in NF1-deficient cells [
62]. In a study on
NF1-mutated ovarian cancer, co-administration of JQ1 and MEKi trametinib proved effective in overcoming the common rapid drug resistance associated with single-agent MEKi [
63]. A second bromodomain inhibitor, bromosporine, demonstrated a superior therapeutic index when combined with MEKi cobimetinib for treating immunotherapy-resistant
NF1-mutant melanoma, compared to MEKi treatment alone [
64•]. More recent work suggests DNMT1 inhibition may be a druggable dependency upon PRC2 loss, providing yet another targeted approach [
65]. Overall, targeting PRC2 loss holds significant promise for enhancing existing strategies for
NF1-deficient tumors by increasing cytotoxicity and limiting the development of drug resistance.