A negative NKX2-1/DUSP6/ERK signal inhibits lung cancer

Lung cancer is the #1 cancer killer in the U.S. Lung cancer’s heterogenous pathology and complicated oncogenic signaling networks have impeded care.

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Lung cancer often originates with activating mutations the RAS signaling pathway.  RAS pathway signaling can also promote the cancer’s progression to high-grade cancer.  However, an even higher level of activity is needed for this progression and negative feedbacks within the pathway initially block this high activity.  Understanding what dismantles these feedback controls during tumor progression will enable the development of new therapeutic approaches to treat lung cancer.  

In our recent manuscript, we found that the lung lineage transcription factor NKX2-1 suppresses RAS pathway activity (Ingram, et al., online Oncogene Oct 23, 2021).  NKX2-1 is expressed in healthy lung, but the expression is frequently silenced in human lung cancer.  We found that NKX2-1 induces the expression of a phosphatase (DUSP6) that inactivates the RAS pathway.  In mouse models of lung cancer, NKX2-1 and the phosphatase inhibit tumor growth and metastasis.  Our results suggest that NKX2-1 downregulation is a mechanism to overcome the RAS pathway feedback signaling and unleash signaling for tumor progression.  Further, they suggest that lung cancers with heterogenous inactivation of NKX2-1 will have non-uniform responses to treatments that manipulate the RAS pathway to induce tumor killing.

Michelle Mendoza

Assistant Professor, University of Utah