Transformational Changes Between Non–Small Cell and Small Cell Lung Cancer—Biological and Clinical Relevance—A Review

Abstract

During the course of therapy, patients with small cell lung cancer have been noted to develop transformation to non–small cell lung cancer and conversely, patients with non–small cell lung cancer have had transformation to small cell lung cancer or other non–small cell histologies. Transformation may occur after prior tyrosine kinase inhibitors, chemotherapy, immunotherapy or radiation therapy. These changes reflect on the overlapping biology of these cell types and the clinical need for re-biopsy at times of disease progression. The optimum therapy after transformation will depend upon prior therapies received, the functional capacity of the patient, and further research to define the best therapy options.

Definitive evidence for Club cells as progenitors for mutant Kras/Trp53‐deficient lung cancer

“…This highly reproducible switch in both lineage‐defining markers and the late onset of Sox2 master transcription factor expression across individual tumors is consistent with the view that initially KP‐transformed Club cells undergo a stereotypic carcinogenic program characterized by lineage marker conversion and the late onset of Sox2 transcription factor expression, involved in oncogenic lineage specification, reprogramming and therapeutic resistance 46‐48 . Thus, in line with the long‐known cellular diversification of human LUAD 51,52 and the recently reported heterogeneous tumor cell states adopted by progressing KP‐transformed AT2 cells, 34,35 our data reveal an inherent plasticity of LUAD‐initiating Club cells. The progressing autonomous diversification of Club cell‐ and AT2 cell‐initiated murine lung tumors may also provide a good explanation why individual LUAD cells can survive an initial anticancer treatment and thus facilitate the development of new therapy‐resistant phenotypes in human patients 57 .…”

“…18,24,26 In contrast to these tance. [46][47][48] Thus, in line with the long-known cellular diversification of human LUAD 51,52 and the recently reported heterogeneous tumor cell states adopted by progressing KP-transformed AT2 cells, 34,35 our data reveal an inherent plasticity of LUAD-initiating Club cells. The progressing autonomous diversification of Club cell-and AT2 cellinitiated murine lung tumors may also provide a good explanation why individual LUAD cells can survive an initial anticancer treatment and thus facilitate the development of new therapy-resistant phenotypes in human patients.…”

“…Human LUAD tumors are reported to change their initial histotype and have the ability to shift lineage marker expression during disease progression and upon therapy 51,52 . In support of additional evidence for histotype plasticity, KP‐transformed murine AT2 lung cancer cells progress through a continued evolution of increased heterogeneity and clonal diversification 34,35 .…”

“…Human LUAD tumors have been reported to change their initial histotype and have the ability to shift lineage marker expression during disease progression and upon therapy 51,52 . To investigate CC10 and SP‐C linage marker expression in human LUAD patients, we analyzed mRNA‐Seq data from The Cancer Genome Atlas (TCGA) 53 .…”

“…Human LUAD tumors have been reported to change their initial histotype and have the ability to shift lineage marker expression during disease progression and upon therapy. 51,52 To investigate CC10…”