| Summary: | MAPK-activated protein kinase 2 (MK2) has diverse roles in cancer. In response to chemotherapy, MK2 inhibition is synthetically lethal to p53-deficiency. While <i>TP53</i> deletion is rare in glioblastomas, these tumors often carry <i>TP53</i> mutations. Here, we show that MK2 inhibition strongly attenuated glioblastoma cell proliferation through p53<sup>wt</sup> stabilization and senescence. The senescence-inducing efficacy of MK2 inhibition was particularly strong when cells were co-treated with the standard-of-care temozolomide. However, MK2 inhibition also increased the stability of p53 mutants and enhanced the proliferation of p53-mutant stem cells. These observations reveal that in response to DNA damaging chemotherapy, targeting MK2 in p53-mutated cells produces a phenotype that is distinct from the p53-deficient phenotype. Thus, MK2 represents a novel drug target in 70% glioblastomas harboring intact <i>TP53</i> gene. However, targeting MK2 in tumors with <i>TP53</i> mutations may accelerate disease progression. These findings are highly relevant since <i>TP53</i> mutations occur in over 50% of all cancers.
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