Researchers discover etiology of SCLC chemoresistance

Because small cell lung cancer (SCLC) develops rapid resistance to chemotherapy, clinical outcomes are resoundingly poor.  Until recently, the mechanisms underlying SCLC’s chemoresistance remained obscure due to the lack of post-relapse tissue samples. Now, in a preclinical study, researchers have discovered that following chemotherapy, SCLC tumors rapidly evolve. Specifically, within weeks to months of chemotherapy,  heightened tumor heterogeneity occurs, resulting in the development of various resistance mechanisms. Full results are published in Nature Cancer.

“Because you end up with a cancer that has multiple resistance mechanisms turned on at the same time in different cells, the cancer becomes much harder to treat,” said principal investigator Lauren Averett Byers, MD, associate professor, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. “Some cells might be resistant through one mechanism or pathway, and other cells might be resistant through a different one. Treatment targeting one type of resistance will only kill a subset of cancer cells.”  

To study intratumoral heterogeneity (ITH), Dr. Byers and colleagues generated circulating tumor cell (CTC)-derived xenografts (CDX) models from patients with SCLC. They then performed single-cell RNA sequencing (RNA-seq) analyses of chemosensitive and chemoresistant CDX models and patient CTCs.

Patient CTCs were placed under the skin of mouse models, which resulted in the development of tumors specific to the patient from which the cells were derived. These CDX models permit the individual assessment of treatment responses to therapy, along with changes that can occur after therapy. 

Currently, a major barrier to the study of SCLC chemoresistance involves the reality that biopsy or surgery isn’t required to confirm SCLC recurrence in most cases. Thus, a paucity of SCLC samples exists on which to conduct genomic and biomarker analysis of drug-resistant tumors, which underscores the importance of the current novel approach.

The researchers discovered global increased ITH among treatment-resistant cell subpopulations after treatment resistance, including heterogeneous expression of therapeutic targets and potential resistance pathways (eg, epithelial-to-mesenchymal transition).

“These findings suggest that treatment resistance in SCLC is characterized by coexisting subpopulations of cells with heterogeneous gene expression leading to multiple, concurrent resistance mechanisms,” wrote the authors. “These findings emphasize the need for clinical efforts to focus on rational combination therapies for treatment-naïve SCLC tumors to maximize initial responses and counteract the emergence of ITH and diverse resistance mechanisms.”

During the course of therapy, they analyzed longitudinal single-cell RNA-seq analyses of CDX models and patient CTCs. 

With resistance onset in each model, Dr. Byers and fellow researchers noted increased ITH and emergence of distinct cellular populations marked by established drug resistance gene signatures. They exposed platinum-sensitive CDX models to prolonged treatment with cisplatin chemotherapy or DNA damage response inhibitors until relapse.

“Longitudinal single-cell profiling of CTCs directly from patient blood before, during and after platinum relapse confirmed increased ITH post-relapse accompanying unique gene expression patterns within specific cell populations that were reflected in a paired CDX,” wrote the authors. 

“These findings suggest that, in response to treatment, SCLC develops increasing transcriptional ITH marked by concurrent, diverse resistant cell clusters. Clinically, these findings underscore the importance of maximizing and maintaining the initial response in platinum-sensitive SCLC tumors, and highlight the intrinsic transcriptional fluidity underlying the profound treatment resistance of SCLC following initial therapy,” they added.

Via the generation of ample CTCs, SCLC liquid biopsies offer a noninvasive means of collection that promotes serial and post-relapse tissue sampling, in addition to single-cell profiling. Intriguingly, one CDX developed spontaneous leptomeningeal disease from a primary flank tumor, which hints at the use of these models in metastatic disease. The authors suggested that utilizing CDXs/CTCs for single-cell analysis may be useful for exploring the role of higher ITH in SCLC treatment resistance.

Although SCLC starts as a near homogenous entity with high response to chemotherapy, it quickly devolves into a pan-resistant disease. The authors suggested that the therapeutic window in SCLC is brief, and aggressive employment of diverse strategies as frontline and maintenance therapies is integral.

“If you look at a lot of the available treatments for relapsed [SCLC], it’s really a minority of patients where you see any response—this study may explain why,” said Dr. Byers. “The next step is to design trials that get drugs to patients earlier, before the cancer has a chance to evolve and become more complex and harder to treat.”