ASCL1 Restrains ERK1/2 to Promote Survival of a Subset of Neuroendocrine Lung Cancers

The transcription factor achaete-scute complexhomolog 1 (ASCL1) is a lineage oncogene that is central in growth and survival of the majority of small cell lung cancers and neuroendocrine (NE) non-small cell lung cancers (NSCLC) that express it. Targeting ASCL1, or its downstream pathways, remains a challenge. Small cell lung cancers and NSCLC-NE that express ASCL1 exhibit relatively low ERK1/2 activity, in dramatic contrast to NSCLCs in which the ERK pathway plays a major role in pathogenesis. ERK1/2 inhibition in ASCL1-expressing lung tumor cells revealed downregulation of ERK1/2 pathway suppressors SPRY4, SPRED1, DUSP6, and the transcription factor ETV5, which regulates DUSP6. Chromatin immunoprecipitation sequencing demonstrated that these genes are bound by ASCL1. Availability of a pharmacologic inhibitor directed mechanistic studies toward DUSP6, an ERK1/2-selective phosphatase, in a subset of ASCL1-high NE lung tumors. Inhibition of DUSP6 increased active ERK1/2, which accumulated in the nucleus. Pharmacologic and genetic inhibition of DUSP6 reduced proliferation and survival of these cancers. Resistance developed in DUSP6-knockout cells, indicating a bypass mechanism. Although targeting ASCL1 remains a challenge, our findings suggest that expression of ASCL1, DUSP6, and low phospho-ERK1/2 identifies NE lung cancers for which DUSP6 may be a therapeutic target.