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bioRxiv · 10.1101/2020.02.25.965004

An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma

Zewdu, R.·Mehrabad, E. M.·Ingram, K.·Jones, A.·Camolotto, S. A.·Mendoza, M. C.·Spike, B. T.·Snyder, E. L.
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Abstract

Cancer cells undergo lineage switching during natural progression and in response to therapy. NKX2-1 loss in human and murine lung adenocarcinoma leads to invasive mucinous adenocarcinoma (IMA), a lung cancer subtype that exhibits gastric differentiation and harbors a distinct spectrum of driver oncogenes. NKX2-1 is required for optimal tumor initiation, but dispensable for growth of established tumors, in BRAFV600E driven disease. NKX2-1-deficient, BRAFV600E driven tumors resemble human IMA and exhibit a distinct response to BRAF/MEK inhibitors. Whereas BRAF/MEK inhibitors drive NKX2-1-positive tumor cells into quiescence, NKX2-1-negative cells fail to exit the cell cycle after the same therapy. BRAF/MEK inhibitors also induce cell identity switching in NKX2-1-negative lung tumors within the gastric lineage, which is driven in part by WNT signaling and FoxA1/2. These data elucidate a complex, reciprocal relationship between lineage specifiers and oncogenic signaling pathways in the regulation of lung adenocarcinoma identity that is likely to impact lineage-specific therapeutic strategies.

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Zewdu, R., Mehrabad, E. M., Ingram, K., Jones, A., Camolotto, S. A., Mendoza, M. C., Spike, B. T., Snyder, E. L.. 2020-02-26. An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma. https://doi.org/10.1101/2020.02.25.965004

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