Lineage plasticity in cancer: a shared pathway of therapeutic resistance

Abstract

Lineage plasticity, the ability of cells to transition from one committed developmental pathway to another, has been proposed as a source of intratumoural heterogeneity and of tumour adaptation to an adverse tumour microenvironment including exposure to targeted anticancer treatments. Tumour cell conversion into a different histological subtype has been associated with a loss of dependency on the original oncogenic driver, leading to therapeutic resistance. A well-known pathway of lineage plasticity in cancer - the histological transformation of adenocarcinomas to aggressive neuroendocrine derivatives - was initially described in lung cancers harbouring an EGFR mutation, and was subsequently reported in multiple other adenocarcinomas, including prostate cancer in the presence of antiandrogens. Squamous transformation is a subsequently identified and less well-characterized pathway of adenocarcinoma escape from suppressive anticancer therapy. The increased practice of tumour re-biopsy upon disease progression has increased the recognition of these mechanisms of resistance and has improved our understanding of the underlying biology. In this Review, we provide an overview of the impact of lineage plasticity on cancer progression and therapy resistance, with a focus on neuroendocrine transformation in lung and prostate tumours. We discuss the current understanding of the molecular drivers of this phenomenon, emerging management strategies and open questions in the field.

Figure 1.

Schematic of how molecular context, lineage plasticity, and treatment-exerted selective pressure can lead to different outcomes, exhibiting exclusive molecular and cellular events for lung (blue) and prostate (yellow) tumors, and commonalities of these processes between both settings (green). In these tumors, a variety of molecular events can promote lineage plasticity, thus triggering intratumoral heterogeneity. A plasticity-permissive molecular environment, together with a selective pressure (i.e., treatment) may lead to intratumoral clones exhibiting an alternative histology to that initially diagnosed, which may become the predominant cell type in the progressed tumor. Colors in the circular figures (cells) represent different intratumoral subclones while shapes represent distinct histologies.

Figure 2.

Prevalent mutations in pre- and post- neuroendocrine transformed lung and prostate adenocarcinoma. (A) Oncoprint showing the most prevalent mutations in post-transformation neuroendocrine lung and prostate tumors from multiple studies^,,,, including pure and mixed histology tumors. (B) Oncoprint showing the most prevalent mutations in lung adenocarcinoma samples that subsequently underwent neuroendocrine-transformation in several studies^,,. (C) Oncoprint showing the mutations detected in matched pre- and post-neuroendocrine transformation cases from . Grey boxes represent unaltered or untested alterations.