Abstract
Lineage transformation between lung cancer subtypes is a poorly understood phenomenon associated with resistance to treatment and poor patient outcomes. Here, we aimed to model this transition to define underlying biological mechanisms and identify potential avenues for therapeutic intervention. Small cell lung cancer (SCLC) is neuroendocrine in identity and, in contrast to non-SCLC (NSCLC), rarely contains mutations that drive the MAPK pathway. Likewise, NSCLCs that transform to SCLC concomitantly with development of therapy resistance downregulate MAPK signaling, suggesting an inverse relationship between pathway activation and lineage state. To test this, we activated MAPK in SCLC through conditional expression of mutant KRAS or EGFR, which revealed suppression of the neuroendocrine differentiation program via ERK. We found that ERK induces the expression of ETS factors that mediate transformation into a NSCLC-like state. ATAC-seq demonstrated ERK-driven changes in chromatin accessibility at putative regulatory regions and global chromatin rewiring at neuroendocrine and ETS transcriptional targets. Further, ERK-mediated induction of ETS factors as well as suppression of neuroendocrine differentiation were dependent on histone acetyltransferase activities of CBP/p300. Overall, we describe how the ERK-CBP/p300-ETS axis promotes a lineage shift between neuroendocrine and non-neuroendocrine lung cancer phenotypes and provide rationale for the disruption of this program during transformation-driven resistance to targeted therapy.
Highlights
Lung cancer, the leading cause of cancer-related mortality worldwide, is divided into two main histological classes, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC)
NSCLCs that transform to Small cell lung cancer (SCLC) concomitantly with development of therapy resistance downregulate mitogen activated protein kinase (MAPK) signaling, suggesting an inverse relationship between pathway activation and lineage state
Previous studies have demonstrated that SCLC and lung adenocarcinoma (LUAD) differ in their expression and activation of MAPK signaling components, and that SCLC-transformed LUAD loses EGFR expression
Summary
The leading cause of cancer-related mortality worldwide, is divided into two main histological classes, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). SCLC is a neuroendocrine (NE) tumor[2] and recent studies have demonstrated that it is a molecularly heterogeneous disease comprising discrete tumor subtypes defined by expression of different transcriptional regulators, namely achaete-scute homolog 1 (ASCL1) and neurogenic differentiation factor 1 (NEUROD1), which together account for approximately 80% of SCLC cases[3, 4]. ASCL1 and NEUROD1, along with insulinoma-associated protein 1 (INSM1) and POU class 3 homeobox 2 (BRN2), are recognized as important master regulators for NE differentiation in SCLC4-6. Besides NE differentiation, SCLC is further distinguished from other major NSCLC subtypes such as lung adenocarcinoma (LUAD) and squamous cell carcinoma by its unique cellular morphology[4] and genetic hallmarks including frequent inactivation of tumor suppressors TP53 and RB17, 8. Elucidating the factors that underlie the selection of specific genetic drivers in different lineage contexts may yield insights towards the development and progression of these lung cancer types
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