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  1. Reviewer #3 (Public Review):

    In the present study, the authors have shown that Nkx2-1 depleted BRAFV600E driven mouse tumors show higher p-ERK activation. MAPK inhibition in these tumors leads to a cellular shift towards the gastric stem and progenitor lineage. The authors have provided detailed mechanistic insights on how MAPK inhibition influences lineage specifiers and oncogenic signaling pathways to form invasive mucinous adenocarcinoma. All experiments are carefully performed and entails advanced research methodologies such as organoid culture systems, novel genetically engineered mouse models and single cell RNA seq. The manuscript is well written, the research findings are logically interpreted and presented. Taken together, all major scientific claims are well supported by the data and offers major technical advancements for the development of precision medicine.

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  2. Reviewer #2 (Public Review):

    In this very extensive and somewhat lengthy manuscript Zewdu et al, characterize an oncogenic Braf-driven model of invasive mucinous lung adenocarcinoma. They show an effect of co-incident and sequential Nkx2-1 inactivation on cancer cells state and therapy responses. They show that BP and BPN tumors have distinct responses to RAF/MEK inhibition. Furthermore, they uncover potentially important cross talk between the MAPK and WNT pathways in invasive mucinous adenocarcinoma (IMA). Overall, this is an excellent manuscript that uncovers many interesting new aspects of IMA. The strengths of this manuscript include the sophisticated in vivo cancer models, detailed cellular analyses, and potential importance of these finds to therapy responses. Their claims are well supported by their data.

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  3. Reviewer #1 (Public Review):

    This manuscript from Eric Snyder's laboratory details cell lineage states that are controlled by NKX2-1 and oncogenic MAPK signaling in BRAFV600E-driven lung cancers. The work builds on previous works from Snyder's group that showed NKX2-1 suppresses a latent gastric differentiation program in KRASG12D-driven lung cancers. Switching the model from KRAS to BRAF, now the Snyder laboratory demonstrates multiple similarities between the oncogenic drivers and details key differences that have significant impact on our understanding of lung cancer etiology and possibly treatment. The depth of data analysis and breadth of methodology used represent a real tour de force in cancer modeling. The insights highlight the complex interplay between mitogenic signaling and developmentally-related pathways during cancer progression. The insights gleaned from the study have some potential in influence treatment strategies. As such, this study will appeal to a broad audience. The stated conclusions from the work are entirely sound and wholly supported by the data presented.

    The authors demonstrate that: Simultaneous activation of BRAFV600E expression and deletion of NKX2-1 suppresses the efficiency of tumor initiation (tumor number goes down). In contrast, genetic deletion of NKX2-1 after tumors have established does not impact tumor maintenance but instead is compatible with tumor progression. Modeling the effects of MAPK pathway inhibition (BRAFi+MEKi), the authors demonstrate that BRAF/p53 (BP) tumors enter a state of quiescence. However, BP tumors with NKX2-1 deletion (BPN) fail to enter the quiescent state. Mechanistically, this is due to activation of a WNT-dependent activation of CyclinD2 that acts with CDK4/6 to suppress RB. Further treatment with CDK4/6 inhibitors can drive cells into quiescence but does not lead to durable tumor growth inhibition as tumors rebound after treatment cessation. Consistent with their previous work in KRAS-driven lung cancers, deletion of NKX2-1 reveals a latent gastric cell differentiation program driven by relocalization of FOX factors toward gastric specific genes. Interestingly, MAPKi in BPN tumors further drives these cells toward a chief-like or tuft-like cell state that is also due to WNT-dependent signaling, and FOXA1/2-dependent effects at specific genes normally restricted to tuft and chief cells.

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  4. Evaluation Summary:

    This manuscript greatly expands our understanding of an aggressive subtype of lung cancer. The author use in vivo cancer models and extensive analysis of the cancer cells states to uncover aspects of differentiation, drug responses and pathway activation. Findings of the study will help in the development of lineage-specific targeted therapies against cancers.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

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  5. Excerpt

    Identifying gastric-like cells in primary lung cancer: Zewdu et al. observe a shift in gastric-like cell signatures after targeted therapy of invasive mucinous adenocarcinoma.

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