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. In murine BRAFV600E-driven lung adenocarcinoma, NKX2-1 is required for early tumorigenesis, but dispensable for established tumor growth. 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 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.
Highlights
Lung adenocarcinoma (LUAD), the most common cause of cancer death worldwide, exhibits significant heterogeneity in tumor cell identity and overall differentiation state (Travis et al 2011)
We have previously shown that Nkx2-1 deletion in KRASG12D driven LUAD leads to invasive mucinous adenocarcinoma (IMA) with high levels of mitogen activated protein kinase (MAPK) activity, as assessed by levels of active ERK1/2
Activation of oncogenic BRAF in the absence of NKX2-1 from alveolar epithelium leads to the development of invasive mucinous adenocarcinoma
Summary
Lung adenocarcinoma (LUAD), the most common cause of cancer death worldwide, exhibits significant heterogeneity in tumor cell identity and overall differentiation state (Travis et al 2011). The majority of LUADs harbor mutually exclusive mutations in driver oncogenes that signal through the mitogen activated protein kinase (MAPK) pathway, including EGFR (14% of cases), KRAS (29%) or BRAF (7%) (early stage cases, reviewed in (Skoulidis and Heymach 2019)). Human IMAs often harbor mutations in KRAS (62% of cases), occasionally BRAF (3%, including point mutations and fusions), but rarely EGFR (0.6%) (Cha and Shim 2017) These studies suggest that there can be selective pressure for LUAD to either retain or downregulate NKX2-1 expression depending on the specific signaling networks activated by a given driver oncogene. Our data show that the level of MAPK pathway activity dictates the specific identity adopted by NKX2-1-negative tumor cells within the gastric lineage This identity shift is mediated in part by WNT signaling, which is increased after MAPK inhibition in IMA models
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
