Abstract 1598: Defining the transcriptional complexity of persister cell populations in relapsed small cell lung cancer patient biopsies

Abstract

Abstract Small cell lung cancer (SCLC) is an aggressive malignancy characterized by robust, however transient, responses to frontline platinum-based therapy that are rapidly followed by refractory relapses. Treatment resistance is a significant concern in SCLC and a major factor regulating resistance is an emergence of unique cellular populations and an increase in intratumoral heterogeneity (ITH). We hypothesize that these emerging populations expressing various resistance-associated pathways, represent multiple, unique drug-resistant persister cell populations that underlie increased ITH and promote therapeutic resistance and, eventually, relapse, despite the initial response to therapy. Persister cells represent a unique population of cancer cells that are resistant to therapeutic pressure. While most persister cells remain arrested under treatment, a rare sub-population exists that can reverse state and re-enter the cell cycle. We performed single cell RNAseq of relapsed, extensive stage SCLC patient paired core biopsies collected 1) following relapse to standard of care (SOC) platinum chemotherapy plus immune checkpoint blockade (ICB) and 2) after six weeks of further therapy. Unlike what we found in platinum-sensitive disease, there is not a meaningful change in ITH score between cancer cells in the first and second biopsy. Presumably, maximum heterogeneity developed along with relapse to SOC treatment. Biopsies represent SCLC across subtypes (SCLC-A/N/P/I) with a modest loss of transcription factor expression following treatment (e.g., 76.8% to 57.9% NEUROD1). Cancer cells were classified as cycling or non-cycling to identify potential persister cell populations in paired patient core biopsies. Molecular subtype marker ASCL1 was reduced in non-cycling cells, but there was no change in NEUROD1 or POU2F3. Cycling cells demonstrate increased expression of NE genes (SYP, INSM1, UCHL1), biomarkers of response (SLFN11 and CDH1), but also genes associated with resistance (EZH2, NFIB). Non-cycling cells exhibit some common resistance mechanisms (e.g., EMT and MYC, AXL, ZFP36L1, and REST overexpression) and increased expression of inflammatory genes (e.g. HLA family) compared to cycling cells, reminiscent of the SCLC-Inflamed (SCLC-I) subtype. These data suggest that non-cycling persister cells may be more sensitive to ICB, AXL and/or AURK inhibition, while cycling cells may be more responsive to platinum chemotherapy, epigenetic modifiers or DNA repair targeted therapies. Clinically, these data underscore the importance of maximizing and maintaining the initial response in platinum-sensitive SCLC tumors, while highlighting the transcriptional complexity underlying SCLC’s profound treatment resistance following SOC and address the major need to develop combination therapies to target these distinct cell populations. Citation Format: C. Allison Stewart, Yuanxin Xi, Runsheng Wang, Michael M. Frumovitz, Jing Wang, Lauren A. Byers, Carl M. Gay. Defining the transcriptional complexity of persister cell populations in relapsed small cell lung cancer patient biopsies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1598.