WINNIPEG, MANITOBA – In the last two decades, targeted therapies have dramatically improved the survival of patients with non-small cell lung cancer (NSCLC) that possess actionable driver mutations.
Most of the patients eventually relapse with drug-resistant disease, according to a report in Cancers (Basel).1
“While various mechanisms of resistance to these targeted therapies have been identified, one common mechanism is histological transformation of the initial NSCLC into small cell lung cancer (SCLC), a histologically distinct subtype of lung cancer,” according to Canadian researchers from the University of Manitoba in Winnipeg. “In this review, we highlight recent advances in our understanding of the mechanisms that drive NSCLC-to-SCLC transformation and how these discoveries have revealed potential therapies to target this mechanism of resistance.”
Lung cancer, the leading cause of cancer-related deaths worldwide, is broadly classified into two histologically distinct subtypes — small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). SCLC is a highly aggressive form of lung cancer that exhibits neuroendocrine histology.
“This mechanism of resistance presents a significant clinical challenge, since there are very few treatments available for these relapsed patients,” the authors pointed out. “Although the phenomenon of NSCLC-to-SCLC transformation was described almost 20 years ago, only recently have we begun to understand the mechanisms underlying this therapy-driven response. These recent discoveries will be key to identifying novel biomarkers and therapeutic strategies to improve outcomes of patients that undergo NSCLC-to-SCLC transformation”
The study highlighted some recent advances and discussed the potential therapeutic strategies that they have uncovered to target that mechanism of resistance. The researchers explained, “SCLC is described as a neuroendocrine (NE) cancer of the lung, whereas NSCLC is primarily of epithelial origin and is further divided into three main subtypes: adenocarcinoma (LUAD), squamous cell carcinoma and large cell carcinoma. Various oncogenic driver mutations have been identified in NSCLC, with some of the most common being activating mutations in epidermal growth factor receptor (EGFR) and fusion proteins involving anaplastic lymphoma kinase (ALK). The discovery of these key oncogenic drivers has spurred the development of various targeted therapies, such as tyrosine kinase inhibitors (TKIs), which have provided significant survival benefits compared to traditional chemotherapy.”
In cases of SCLC transformation (also referred to as small cell transformation or NE transformation) relapsed tumors “undergo significant molecular and histological changes and exhibit many classical characteristics of SCLC, such as high nuclear-to-cytoplasmic ratio, expression of NE markers and inactivation of the RB1 and p53 tumor suppressors. Importantly, the transformed SCLC tumors retain the initial oncogenic mutation found in the original NSCLC, highlighting the likelihood of direct evolution of the initial NSCLC,” according to the study.
Instances of NSCLC-to-SCLC transformation are called transformed SCLC, or T-SCLC, to distinguish them from SCLC that arises de novo. “Unfortunately, there are few treatment options for patients with T-SCLC, which results in very poor outcomes for these patients,” the researchers advised. “Developing a better understanding of the mechanisms that drive NSCLC-to-SCLC transformation will ultimately identify novel treatment strategies to improve outcomes for these patients. However, we have only recently begun to understand these mechanisms and how they may inform clinical intervention. In this review, we highlight these recent advances and discuss the potential therapeutic opportunities that they have uncovered.
1.Joshi A, Bhaskar N, Pearson JD. Neuroendocrine Transformation as a Mechanism of Resistance to Targeted Lung Cancer Therapies: Emerging Mechanisms and Their Therapeutic Implications. Cancers (Basel). 2025 Jan 15;17(2):260. doi: 10.3390/cancers17020260. PMID: 39858043; PMCID: PMC11763869.
