Abstract 162P
Background
Small cell lung cancer (SCLC) is a high grade neuroendocrine tumor accounting for ∼15% of all lung cancers. Whilst MAPK mutations can be found in roughly 30% of human cancers including non-small cell lung cancer (NSCLC), genomic and proteomic analyses have indicated suppression of MAPK pathway activity in SCLC. This striking difference is not well understood and previous attempts to determine whether this might be therapeutically important have had conflicting conclusions. SCLC has recently been defined by the relative expression of four major transcriptional regulators (ASCL1, NeuroD1, POU2F3, YAP1). In this study, we aimed to elucidate the effect of MAPK activation in these different SCLC subtypes and explore its therapeutic vulnerability.
Methods
We used a doxycycline-inducible vector for expression of MEKDDS217D/S221D (MEK1) in a cohort of ASCL1-, NEUROD1, POU2F3- and YAP1-driven cell lines and mouse models.
Results
Activation through MEK1in ASCL1-driven SCLC cell lines resulted in a significant decrease in cell growth over 9 days. This was associated with a decrease in neuroendocrine markers ASCL1 and INSM1, and a G2 cell cycle arrest. Remarkably, athymic mice injected with a MEK1-expressing ASCL1-driven cell line showed significantly slower tumor formation and longer survival than the ASCL1-driven cell line not expressing MEK1. We observed strong upregulation of DUSP6, SPRY2, but not ETV5 upon MAPK activation. Phosphokinase array in all four subtype cell lines after MEK1 activation demonstrated that, almost exclusively, the STAT pathways, in particular, STAT3 through phosphorylation at S727 were strongly upregulated in the ASCL1-driven subtype. Upon treatment with a STAT3 inhibitor, Stattic (1μM), ASCL1-driven SCLC cells reached their IC50 after 3–5 days in comparison to 9 days for other SCLC subtypes. NSCLC cell line was resistant to STAT3 inhibition.
Conclusions
We show that ASCL1-driven SCLC in vitro and in vivo is sensitive to activation of MAPK signaling in comparison to other SCLC subtypes. Whilst activation of the MAPK pathway might seem counterintuitive to current treatment strategies that aim to inhibit oncogenic signaling, we propose the use of a STAT3 inhibitor that has shown to be effective in vitro.
Legal entity responsible for the study
The author.
Funding
Has not received any funding.
Disclosure
The author has declared no conflicts of interest.