Abstract
Poorly differentiated tumors in non-small cell lung cancer (NSCLC) have been associated with shorter patient survival and shorter time to recurrence following treatment. Here, we integrate multiple experimental models with clinicopathologic analysis of patient tumors to delineate a cellular hierarchy in NSCLC. We show that the oncofetal protein 5T4 is expressed on tumor-initiating cells and associated with worse clinical outcome in NSCLC. Coexpression of 5T4 and factors involved in the epithelial-to-mesenchymal transition were observed in undifferentiated but not in differentiated tumor cells. Despite heterogeneous expression of 5T4 in NSCLC patient-derived xenografts, treatment with an anti-5T4 antibody-drug conjugate resulted in complete and sustained tumor regression. Thus, the aggressive growth of heterogeneous solid tumors can be blocked by therapeutic agents that target a subpopulation of cells near the top of the cellular hierarchy.
Highlights
Non–small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths, due to high incidence and lack of effective therapies [1]
The degree of tumor cell differentiation is an independent prognostic factor for clinical outcome, as less differentiated tumors are associated with increased risk of death in both squamous cell carcinoma and adenocarcinoma [5]
We show preclinical efficacy of an anti-5T4 antibody–drug conjugate (ADC) and suggest that this therapeutic strategy could be applied to other surface markers expressed on tumor-initiating cells (TIC)
Summary
Non–small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths, due to high incidence and lack of effective therapies [1]. NSCLC has heterogeneous pathologies and molecular profiles, which presents challenges to molecular targeting and treatment [2,3,4]. The degree of tumor cell differentiation is an independent prognostic factor for clinical outcome, as less differentiated tumors are associated with increased risk of death in both squamous cell carcinoma and adenocarcinoma [5]. Less differentiated tumors are associated with increased risk of recurrence after resection [5]. The molecular and cellular bases for these associations are not understood. Investigation of the cellular heterogeneity in tumors has encouraged new frameworks, such as the cancer stem cell
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