Oncogenic KRAS/ERK/JUNB signaling suppresses differentiation regulator GATA6 in pancreatic cancer
Zheng Zhong, Xinang Cao, Pei-Ju Liao, Raman Sethi, Jeffrey A. Klomp, Clint A. Stalnecker, Jinmiao Chen, Yue Wan, Channing J. Der, David M. Virshup
Zheng Zhong, Xinang Cao, Pei-Ju Liao, Raman Sethi, Jeffrey A. Klomp, Clint A. Stalnecker, Jinmiao Chen, Yue Wan, Channing J. Der, David M. Virshup
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Research Article Cell biology Oncology

Oncogenic KRAS/ERK/JUNB signaling suppresses differentiation regulator GATA6 in pancreatic cancer

Abstract

GATA6 is a master regulator of differentiation in the pancreas, and its expression levels determine the 2 main molecular subtypes of pancreatic cancer. High GATA6 levels contribute to the classical pancreatic cancer subtype, which is associated with a higher degree of tumor differentiation and better disease prognosis. However, why GATA6 expression varies across pancreatic cancers and what regulates GATA6 expression remain elusive. Here, we report that oncogenic KRAS-activated ERK signaling suppresses GATA6 transcription in pancreatic cancers. GATA6 mRNA levels inversely correlated with KRAS/ERK activity in pancreatic tumors. A genome-wide CRISPR screen in a GATA6-EGFP reporter knockin cell line identified JUNB as the ERK-regulated transcriptional repressor for GATA6. Active ERK stabilized JUNB protein, while KRAS/ERK inhibition led to ubiquitin-independent proteasomal degradation of JUNB and increased transcription of GATA6. Upregulation of GATA6 enhanced chemosensitivity of pancreatic cancer cells, and KRAS/ERK inhibitors synergized with chemotherapy in a GATA6-dependent manner. Our study identifies how oncogenic KRAS/ERK signaling suppresses GATA6 to cause dedifferentiation in pancreatic cancer. Combining KRAS/ERK inhibitors with standard-of-care chemotherapies could be a promising therapeutic strategy for treating pancreatic cancers.

Authors

Zheng Zhong, Xinang Cao, Pei-Ju Liao, Raman Sethi, Jeffrey A. Klomp, Clint A. Stalnecker, Jinmiao Chen, Yue Wan, Channing J. Der, David M. Virshup

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Figure 10

KRAS/ERK inhibition synergizes with oxaliplatin in pancreatic cancer models.

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KRAS/ERK inhibition synergizes with oxaliplatin in pancreatic cancer mod...
(A) GATA6-dependent drug synergy between oxaliplatin and KRAS/MEK/ERK inhibitors. Drug combination effects between oxaliplatin and the MEK inhibitor trametinib or the KRASG12D inhibitor MRTX1133 were examined for GATA6 WT or knockout HPAF-II cells following the Chou-Talalay protocol. The fraction affected refers to growth inhibitory effects of the drug combinations (0, no inhibition; 1, 100% inhibition), and the corresponding log10-transformed Combination Index values are shown. The smaller the Combination Index value, the stronger the drug synergism. (B and C) Trametinib and oxaliplatin combination treatment potently inhibited pancreatic tumor growth in xenograft models. (B) Mice bearing Panc08.13 subcutaneous xenografts were treated with vehicle, trametinib (1.5 mg/kg per dose, twice weekly), oxaliplatin (5 mg/kg per dose, once weekly), or the combination of trametinib and oxaliplatin (combo) for 2 weeks. n = 9–12 tumors per arm. Data are shown as the mean ± SEM. (C) Mice bearing HPAF-II orthotopic xenografts were treated with vehicle, trametinib (0.5 mg/kg per dose × 10 doses administered over 4 weeks), oxaliplatin (5 mg/kg per dose, twice weekly), or the combination of trametinib and oxaliplatin (combo) for 4 weeks. n = 8–10 tumors per arm. P values of 2-tailed, unpaired t test are shown.