HNF4α controls growth, identity, and KRAS inhibitor response in invasive mucinous adenocarcinoma of the lung
Headtlove Essel Dadzie, Yangsook Song Green, Soledad A. Camolotto, Henry U. Arnold, Matthew Gumbleton, Minzhe Guo, Mari Mino-Kenudson, Yutaka Maeda, Benjamin T. Spike, Eric L. Snyder
Headtlove Essel Dadzie, Yangsook Song Green, Soledad A. Camolotto, Henry U. Arnold, Matthew Gumbleton, Minzhe Guo, Mari Mino-Kenudson, Yutaka Maeda, Benjamin T. Spike, Eric L. Snyder
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Research Article Oncology Pulmonology

HNF4α controls growth, identity, and KRAS inhibitor response in invasive mucinous adenocarcinoma of the lung

Abstract

Cellular plasticity is a hallmark of cancer, enabling tumor cells to alter identity and evade therapeutic pressure. In invasive mucinous adenocarcinoma of the lung (IMA), NK2 homeobox 1 (NKX2-1) loss triggers a pulmonary to gastric switch marked by aberrant activation of hepatocyte nuclear factor 4 alpha (HNF4α), a master regulator of gastrointestinal/hepatic differentiation. We show that HNF4α promoted IMA growth and activated a gastric pit cell–like program. Loss of HNF4α enabled forkhead box A1 and A2 (FoxA1/2) transcription factors to bind de novo sites and activate alternative, nongastric identities in IMA. HNF4α also established a mucinous program associated with tolerance to KRAS blockade, and loss of HNF4α enhanced response to KRASG12D inhibition. Mechanistically, HNF4α blocked cell-cycle exit in drug-tolerant persister cells and promoted activity of the antioxidant transcription factor nuclear factor erythroid 2–related factor 2 (NRF2). NRF2 activation partially rescued the effects of Hnf4a deletion on KRASG12D inhibition, whereas NRF2 inhibition enhanced sensitivity to KRASG12D blockade. Thus, HNF4α is a key regulator of growth, identity, and primary response to KRASG12D inhibition in IMA.

Authors

Headtlove Essel Dadzie, Yangsook Song Green, Soledad A. Camolotto, Henry U. Arnold, Matthew Gumbleton, Minzhe Guo, Mari Mino-Kenudson, Yutaka Maeda, Benjamin T. Spike, Eric L. Snyder

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Figure 2

HNF4α directly binds and activates gastric lineage programs in IMA.

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HNF4α directly binds and activates gastric lineage programs in IMA. (A) ...
(A) Genome-wide HNF4α ChIP-seq occupancy in KN tumors. (B) HOMER motif enrichment of HNF4α-bound peaks in KN tumors. (C) ENRICHR ARCHS4 tissue enrichment of genes annotated from HNF4α peaks in KN tumors. (D) Overlap between bulk RNA-seq DEGs and genes annotated from HNF4α peaks in GEMM tumors. Down, downregulated; Up, upregulated. (E) Distribution of HNF4α-bound peaks defined by integration of HNF4α ChIP-seq and H3K27ac HiChIP and annotated to the 86 genes shared with in vivo downregulated DEGs, stratified by looping to promoters, enhancers, or both. (F and G) Integrative Genome Visualization (IGV) tracks showing HNF4α occupancy at gastric lineage genes (F) and lack of occupancy at pulmonary lineage genes (G) in KN tumors. (H) HOMER motif enrichment of HNF4α-bound peaks in HCI_IMA03. (I and J) IGV tracks showing HNF4α occupancy at gastric lineage genes (I) and lack of occupancy at pulmonary lineage genes (J) in HCI_IMA03. (K) ENRICHR ARCHS4 tissue enrichment of genes annotated from HNF4α peaks in HCI_IMA03.