Small cell transformation of ROS1 fusion-positive lung cancer resistant to ROS1 inhibition

Jessica J Lin,Isobel J Fetter,Emily Chin,Dejan Juric,Aaron N Hata,Kylie Prutisto-Chang ,Justin F Gainor,Satoshi Yoda,Marguerite Rooney,Audris Oh ,Ryan B Corcoran,James R Stone,Adam Langenbucher,Marina Kem,Michael S Lawrence,Andrew Do,Ibiayi Dagogo‐Jack ,Mari Mino–Kenudson ,Jochen K Lennerz,Pranav Gupta,Alice T Shaw

doi:10.1038/s41698-020-0127-9

Jessica J Lin, Isobel J Fetter + Show 19 more

Open Access

https://doi.org/10.1038/s41698-020-0127-9

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Abstract

Histologic transformation from non-small cell to small cell lung cancer has been reported as a resistance mechanism to targeted therapy in EGFR-mutant and ALK fusion-positive lung cancers. Whether small cell transformation occurs in other oncogene-driven lung cancers remains unknown. Here we analyzed the genomic landscape of two pre-mortem and 11 post-mortem metastatic tumors collected from an advanced, ROS1 fusion-positive lung cancer patient, who had received sequential ROS1 inhibitors. Evidence of small cell transformation was observed in all metastatic sites at autopsy, with inactivation of RB1 and TP53, and loss of ROS1 fusion expression. Whole-exome sequencing revealed minimal mutational and copy number heterogeneity, suggestive of “hard” clonal sweep. Patient-derived models generated from autopsy retained features consistent with small cell lung cancer and demonstrated resistance to ROS1 inhibitors. This case supports small cell transformation as a recurring resistance mechanism, and underscores the importance of elucidating its biology to expand therapeutic opportunities.

Highlights

Gene fusions involving the ROS1 proto-oncogene 1 (ROS1) are oncogenic drivers across multiple tumor types, including non-small cell lung cancer (NSCLC)[1,2,3,4]
We present the analysis of metastatic tumor samples collected from a patient with advanced ROS1+ NSCLC who had received multiple ROS1 inhibitors during her treatment course
Evidence of small cell transformation was observed in all metastatic tumor samples harvested at autopsy

Summary

Introduction

Gene fusions involving the ROS1 proto-oncogene 1 (ROS1) are oncogenic drivers across multiple tumor types, including non-small cell lung cancer (NSCLC)[1,2,3,4]. Targeted therapy with ROS1 tyrosine kinase inhibitors (TKIs) such as crizotinib and entrectinib usually yields deep and durable tumor responses in ROS1 fusion-positive (ROS1+) lung cancer[5,6,7,8,9]. Initial studies of crizotinib resistance in ROS1+ NSCLC have focused on secondary ROS1 kinase domain mutations (KDMs), such as ROS1. Tumor lineage changes, including epithelial-to-mesenchymal transition (EMT) or histologic transformation into small cell lung cancer (SCLC), represent a target-independent TKI resistance mechanism[15]. Small cell transformation has been identified in ~3–10% of TKI-resistant, EGFR-mutant NSCLC, and is associated with an aggressive clinical phenotype, limited therapy options, and poor prognosis[16,17,18,19,20,21]. We show that resistance was due to small cell transformation and describe the genomic landscape and clonal evolution of the transformed lung cancer

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