Relapse to MAp. pathway inhibitors (such as BRAF, MEK, and KRAS inhibitors) is common due to the reactivation of ERK and MAPK signaling. In this First Disclosure, Wallis, Munck, and colleagues outline the ERK inhibitor ASTX029. ASTX029 inhibits both the phosphorylation of ERK by MEK as well as its catalytic activity and, therefore, is categorized as a dual-mechanism inhibitor by the authors. The dual-mechanism ERK inhibitor demonstrated anti-tumor activity to MAPK inhibitor-resistant cancers in vitro and in vivo. Their work supports the continued clinical development of ASTX029 in advanced solid tumors.

The specific DNA damage O6-methylguanine induced by temozolomide was quantified and set in relation to double-strand breaks, apoptosis and senescence. The findings challenged the model of DNA damage thresholding as O6-methylguanine induced these endpoints in glioblastoma cells without a no-effect threshold. Interestingly, senescence appears to occur at a much lower number of O6-methylguanine...

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