ABSTRACT
The tumor suppressor LKB1 is a serine/threonine protein kinase that is frequently mutated in human lung adenocarcinoma (LUAD). LKB1 regulates a complex signaling network that is known to control cell polarity and metabolism; however, the pathways that mediate the tumor-suppressive activity of LKB1 are incompletely defined. To identify mechanisms of LKB1-mediated growth suppression, we developed a spheroid-based cell culture assay to study LKB1-dependent growth. We then performed genome-wide CRISPR screens in spheroidal culture and found that LKB1 suppresses growth, in part, by activating the PIKFYVE lipid kinase. Finally, we used chemical inhibitors and a pH-sensitive reporter to determine that LKB1 impairs growth by promoting the internalization of wild-type EGFR in a PIKFYVE-dependent manner.
Subject(s)
AMP-Activated Protein Kinase Kinases , Phosphatidylinositol 3-Kinases , Protein Serine-Threonine Kinases , Spheroids, Cellular , Humans , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , AMP-Activated Protein Kinase Kinases/metabolism , AMP-Activated Protein Kinase Kinases/genetics , Spheroids, Cellular/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol 3-Kinases/genetics , Cell Proliferation , Cell Line, Tumor , CRISPR-Cas Systems , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lung Neoplasms/metabolism , Clustered Regularly Interspaced Short Palindromic Repeats/geneticsABSTRACT
Lung adenocarcinoma (LUAD) and small cell lung cancer (SCLC) are thought to originate from different epithelial cell types in the lung. Intriguingly, LUAD can histologically transform into SCLC after treatment with targeted therapies. In this study, we designed models to follow the conversion of LUAD to SCLC and found that the barrier to histological transformation converges on tolerance to Myc, which we implicate as a lineage-specific driver of the pulmonary neuroendocrine cell. Histological transformations are frequently accompanied by activation of the Akt pathway. Manipulating this pathway permitted tolerance to Myc as an oncogenic driver, producing rare, stem-like cells that transcriptionally resemble the pulmonary basal lineage. These findings suggest that histological transformation may require the plasticity inherent to the basal stem cell, enabling tolerance to previously incompatible oncogenic driver programs.
Subject(s)
Adenocarcinoma of Lung , Lung Neoplasms , Proto-Oncogene Proteins c-akt , Proto-Oncogene Proteins c-myc , Small Cell Lung Carcinoma , Humans , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/pathology , Adenocarcinoma of Lung/therapy , Epithelial Cells/pathology , Lung/pathology , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lung Neoplasms/therapy , Small Cell Lung Carcinoma/genetics , Small Cell Lung Carcinoma/pathology , Small Cell Lung Carcinoma/therapy , Oncogenes , Cell Lineage , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-akt/genetics , Molecular Targeted TherapyABSTRACT
The tumor suppressor LKB1 is a serine/threonine protein kinase that is frequently mutated in human lung adenocarcinoma (LUAD). LKB1 regulates a complex signaling network that is known to control cell polarity and metabolism; however, the pathways that mediate the tumor suppressive activity of LKB1 are incompletely defined. To identify mechanisms of LKB1- mediated growth suppression we developed a spheroid-based cell culture assay to study LKB1- dependent growth. Using this assay, along with genome-wide CRISPR screens and validation with orthogonal methods, we discovered that LKB1 suppresses growth, in part, by activating the PIKFYVE lipid kinase, which promotes the internalization of wild-type EGFR. Our findings reveal a new mechanism of regulation of EGFR, which may have implications for the treatment of LKB1 -mutant LUAD.
ABSTRACT
OBJECTIVES: To explore the impact of pre-existing comorbidities on immunotherapy response, overall and progression-free survival, and immune-related adverse events (irAEs) of patients with advanced head and neck cancer (HNC) treated with immunotherapy. PATIENTS AND METHODS: Ninety-three patients treated with immunotherapy were identified and stratified into comorbidity absent or present (CCI < 1 and CCI ≥ 1, respectively) cohorts, and clinical outcomes were compared between these two groups. RESULTS: Patients with no comorbidities had longer overall survival (aHR = 2.74, 95% CI [1.18, 6.40], p = 0.02) and progression-free survival (aHR = 2.07, 95% CI [1.03, 4.16], p = 0.04) and a higher tumor response rate (32% in CCI < 1 vs. 14% in CC ≥ 1, p = 0.05). Risk for irAEs was higher in the comorbidity absent group (p = 0.05). CONCLUSION: Comorbidity should be considered as a significant prognostic factor in clinical decision-making for patients with advanced HNC undergoing immunotherapy.
Subject(s)
Head and Neck Neoplasms , Humans , Prognosis , Head and Neck Neoplasms/therapy , Comorbidity , Progression-Free Survival , Immunotherapy/adverse effects , Retrospective StudiesABSTRACT
The CEA family comprises 18 genes and 11 pseudogenes located at chromosome 19q13.2 and is divided into two main groups: cell surface anchored CEA-related cell adhesion molecules (CEACAMs) and the secreted pregnancy-specific glycoproteins (PSGs). CEACAMs are highly glycosylated cell surface anchored, intracellular, and intercellular signaling molecules with diverse functions, from cell differentiation and transformation to modulating immune responses associated with infection, inflammation, and cancer. In this review, we explore current knowledge surrounding CEACAM1, CEACAM5, and CEACAM6, highlight their pathological significance in the areas of cancer biology, immunology, and inflammatory disease, and describe the utility of murine models in exploring questions related to these proteins.
