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 1

HNF4α is essential for in vivo growth of established IMA.

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HNF4α is essential for in vivo growth of established IMA. (A) Representa...
(A) Representative H&E and IHC images for NKX2-1 and HNF4α in IMA GEMMs expressing Hnf4a+/+, Hnf4afl/+, and Hnf4afl/fl. Scale bar: 100 μm. (B) Tumor burden in Hnf4a+/+ (n = 5), Hnf4afl/+ (n = 6), and Hnf4afl/fl (n = 5) GEMMs 14 weeks PTI with Ad5mSPC-FlpO (1 × 108 PFU/mouse). **P < 0.01, by Mann-Whitney U test. (C) Quantification of cleaved caspase 3 (CC3) in KN and KNH GEMMs 1 week (left) or 8 weeks (right) after first i.p. dose of tamoxifen. #P = 0.0123; ****P < 0.0001, by unpaired, 2-tailed Student’s t test. (D) Representative immunoblots for the indicated proteins in KN and KNH of 1311G and 429A organoids. (E) Longitudinal s.c. tumor volume of 1311G organoids in NSG mice. *P < 0.05 and **P < 0.01, by unpaired, 2-tailed Student’s t test. (F) Fold change in 429A s.c. tumor volume in NRG mice after 10 days of tamoxifen. ###P = 0.0004, by unpaired, 2-tailed Student’s t test. (G) Endpoint tumor mass of KN and KNH tumors from NSG or NRG mice transplanted with 1311G (left, †P = 0.0013) or 429A (right, ††P = 0.0030) organoids; unpaired, 2-tailed Student’s t test. (H) Representative H&E and IHC images of NKX2-1 and HNF4α staining in s.c. tumors generated from isogenic 1311G KN and KNH organoids in NSG mice. Scale bar: 100 μm.