*October 2025*
Highlights
- Clinical Impact of Histological Transformation NSCLC-to-SCLC transformation drives resistance to targeted and immune therapies in EGFR-mutant cases, leading to aggressive disease with poor outcomes that demands new management approaches.
- Mechanisms Driving Transformation RB1/TP53 loss enables transformation through lineage plasticity, supported by APOBEC hypermutation and dysregulation of MYC, NOTCH and epigenetic pathways.
- Hypotheses of Transformation Both cellular reprogramming under therapy pressure and selection of pre-existing clones contribute to histological transformation, with ongoing debate about their relative roles.
- Therapeutic Challenges and Emerging Strategies While chemotherapy remains standard, its benefits are limited. Emerging targeted therapies against DLL3 and AURKA show potential to improve outcomes.
- Future Directions Future work must focus on predictive biomarkers, plasticity-targeting drugs, and better detection methods to address this challenging resistance mechanism.
1. Introduction
Lung cancer remains the most prevalent malignancy and leading cause of cancer-related mortality worldwide. The World Health Organization (WHO) classifies lung cancer into two major histological subtypes: non-small cell lung cancer (NSCLC), accounting for approximately 85 % of cases, and high-grade neuroendocrine carcinoma (HGNEC), which constitutes the remaining 15 % [1]. NSCLC is further categorized into adenocarcinoma (LUAD), squamous cell carcinoma (LUSC), and sarcomatoid carcinoma, whereas HGNEC includes small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma. The treatment of lung cancer with different histological types has always been a focal point for researchers. Surgery, radiation therapy, chemotherapy, immunotherapy, and molecularly targeted therapies are used to treat NSCLC [2]. In recent years, significant advancements in targeted therapies and immune checkpoint inhibitors have markedly improved clinical outcomes. However, the development of drug resistance remains a major therapeutic challenge. Tumor cells employ diverse mechanisms to evade targeted agents, including genetic alterations and phenotypic plasticity [3]. Notably, histological transformation—particularly from NSCLC to SCLC—has emerged as a key resistance mechanism in patients receiving EGFR/ALK/ROS1 tyrosine kinase inhibitors (TKIs) or immunotherapy [4]. Despite its clinical relevance, the underlying mechanisms, clinical manifestations, and optimal management strategies for histological transformation remain poorly understood. This review evaluates two prevailing mechanistic hypotheses underlying histological transformation in lung cancer, while systematically synthesizing current evidence on its molecular drivers and clinical implications – with particular focus on the well-documented NSCLC-to-SCLC transition. Additionally, we discuss emerging therapeutic approaches for transformed malignancies, aiming to provide a comprehensive resource for researchers and clinicians.
2. Clinical landscape of histological transformation as a resistance mechanism in lung cancers
Targeted molecular therapies, including EGFR-TKIs and ALK-TKIs, have markedly improved survival outcomes in patients with advanced EGFR/ALK-mutant NSCLC [5]. Concurrently, immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have revolutionized treatment for driver-negative NSCLC. Nevertheless, acquired resistance to both targeted therapies and ICIs persists as a major clinical challenge [6,7]. Histological transformation from NSCLC to SCLC has emerged as a pivotal resistance mechanism against EGFR-TKIs [8,9], with reported incidence rates of 5–14 % in patients receiving first- or second-generation inhibitors [10]. Emerging evidence underscores critical clinicopathological distinctions between transformed SCLC (T-SCLC) and de novo SCLC. T-SCLC predominantly occurs in never/light-smoking EGFR-mutant patients, contrasting sharply with the strong smoking association characteristic of de novo SCLC [11,12]. Clinically, T-SCLC demonstrates more aggressive behavior, exhibiting shorter median progression-free survival (4.1 vs 6.7 months) and overall survival (8.9 vs 12.4 months) with chemotherapy compared to de novo cases [13,14]. Molecular analyses reveal that while T-SCLC maintains the original EGFR mutation, it acquires characteristic RB1/TP53 co-deletions – a genomic signature distinct from the MYC-driven pathways predominant in de novo SCLC [15]. Transformation from LUAD to LUSC following EGFR-TKI therapy remains uncommon, with documented incidence below 5 %, although 9–14 % of EGFR-mutant LUADs progress to high-grade neuroendocrine tumors [16,17]. Several notable cases illustrate this phenomenon: Kaiho et al. [18] reported ALK-rearranged LUAD transforming to LUSC after alectinib treatment, while Gazeu et al. [19] described RET-rearranged LUAD evolving into SCLC during pralsetinib therapy. The recognition of immunotherapy-induced transformation is growing. Shen et al. [20] documented two cases of LUSC transforming to SCLC during anti-PD-1 therapy, and Li et al. [21] reported a similar transformation following neoadjuvant immunotherapy. Importantly, the true incidence of histological transformation may be substantially underestimated due to limited acquisition of post-progression biopsy specimens. Given the profound diagnostic and therapeutic implications of histological transformation, rigorous investigation into its underlying molecular mechanisms is urgently needed.
3. Hypothetical mechanisms underlying histological transformation
Recent advances in research have elucidated two predominant hypotheses to explain histological transformation in lung cancer, as evidenced by varying histological patterns in repeat biopsies (Fig. 3).
3.1. Lineage plasticity hypothesis
The lineage plasticity hypothesis proposes that NSCLC and SCLC may originate from a common cancer stem cell precursor. This model suggests that under selective pressure from targeted therapies or immunotherapy, NSCLC cells can undergo transdifferentiation into SCLC, and vice versa [5]. In the specific context of EGFR-mutant LUAD transforming to SCLC, current evidence indicates both tumor types likely derive from alveolar type II cells. This phenomenon of tumor cell plasticity enables cancer cells to reversibly alter their lineage identity and differentiation state in response to therapeutic pressures, thereby evading targeted treatments. Strong support for this hypothesis comes from molecular analyses demonstrating that transformed SCLC frequently retains the original EGFR mutations present in the precursor adenocarcinoma. A representative case involved a patient with EGFR exon 19 deletion-positive LUAD that transformed to SCLC after 20 months of treatment, with genetic confirmation of the persisting EGFR mutation [22]. L. Ferrer et al. conducted a multicenter retrospective analysis of 48 patients with EGFR-mutant NSCLC, revealing that 84 % of cases maintained the same EGFR mutation post-transformation [23]. The exceptional rarity of EGFR mutations in de novo SCLC strongly suggests that EGFR-mutant SCLC cases likely represent transformed NSCLC rather than de novo SCLC.
3.2. Tumor heterogeneity hypothesis
An alternative explanation, the tumor heterogeneity hypothesis, posits that pretreatment tumors may already contain both NSCLC and SCLC components. According to this view, targeted therapies selectively suppress the NSCLC population, allowing pre-existing SCLC clones to dominate in subsequent biopsies. However, this hypothesis faces significant challenges. Given the established resistance of de novo SCLC to EGFR-TKIs, it becomes difficult to explain the initial treatment responses observed in many cases [23]. Furthermore, clinical data from Offin et al. demonstrate a median transformation latency of 1.1 years following EGFR-TKI initiation [24], a timeline inconsistent with simple selection of pre-existing resistant clones. These observations collectively suggest that lineage plasticity, rather than clonal selection, better explains the phenomenon of histological transformation.
Two prevailing hypotheses, the lineage plasticity hypothesis and tumor heterogeneity hypothesis, offer distinct yet complementary explanations for histological transformation in lung cancer, each supported by compelling clinical and molecular evidence. The lineage plasticity hypothesis posits that cancer cells dynamically switch identities (e.g., from adenocarcinoma to small-cell or squamous histology) under therapeutic pressure, often mediated by transcriptional/epigenetic reprogramming [[25], [26], [27]]. This is substantiated by observations below. (1) rapid histological shifts post-therapy (e.g., EGFR-mutant LUAD to SCLC without clonal selection [28], (2) conserved driver mutations (e.g., EGFR retention) despite lineage changes [29], and (3) experimental models showing induced plasticity via lineage specifier loss [27]. Clinically, this suggests transformation may occur de novo during treatment, necessitating frequent re-biopsies to detect emergent phenotypes early [30].
In contrast, the tumor heterogeneity hypothesis maintains that pre-existing minor subclones with divergent differentiation potential undergo selective expansion under therapeutic pressure [31,32]. This paradigm is supported by: (1) documented genomic divergence between primary and transformed lesions [33], (2) delayed transformation timelines consistent with clonal evolution [31], and (3) spatial transcriptional heterogeneity in untreated tumors [34,35]. From a clinical perspective, this mechanism implies the importance of strategic re-biopsy timing aligned with resistance development, multi-region sampling approaches to characterize pre-existing diversity, and longitudinal genomic surveillance to track clonal selection patterns.
4. Lineage plasticity in lung cancer: Gene mutations and signaling pathways in histological transformation
4.1. Cellular origins of lung cancer and implications for lineage plasticity
To understand the molecular mechanisms underlying lineage plasticity-mediated histological transformation in lung cancer, we must first examine the cellular origins of different lung epithelial populations. Emerging evidence from developmental biology studies provides compelling support for the fundamental principles of cellular plasticity in pulmonary tissues.
The respiratory epithelium comprises diverse cell types including basal cells, club (Clara) cells, neuroendocrine cells, ciliated cells, goblet cells, and type I/II alveolar cells (Fig. 1). Genetically engineered mouse models (GEMMs) have significantly advanced our understanding of the cellular origins of various lung cancer subtypes [36]. Activating mutations in KRAS represent a pivotal early event in LUAD tumorigenesis, with type II alveolar cells (AT2) established as the primary cell of origin. However, accumulating evidence suggests club cells may also contribute to LUAD development [[36], [37], [38]]. In contrast, LUSC has traditionally been associated with tracheobronchial basal cells, as evidenced by p63 expression, though studies demonstrate potential origins from AT2 and club cells as well [39,40]. SCLC, while predominantly arising from neuroendocrine cells, exhibits remarkable lineage plasticity with demonstrated origins from basal, club, and AT2 cells [41,42]. Research utilizing mouse models has revealed that a variety of cellular lineages within the lung can initiate the diverse subtypes of lung cancer. The cell of origin is closely linked to tumor subtype, but there are also many instances of mutual transformation. SCLC originates from various cellular lineages, with neuroendocrine cells serving as a significant cell of origin, particularly following the loss of Rb1 and Trp53. Sutherland and team’s investigation in Trp53F/F;Rb1F/F mice revealed that the deployment of adenoviral vectors, specifically engineered to express Cre recombinase under the SPC promoter (Ad5-SPC-Cre), can selectively ablate Rb1 and Trp53 in AT2 cells, thereby triggering SCLC development [43]. Certain genetic factors can either propel or hinder the transformation between specific subtypes of lung cancer, revealing that its histological presentation is plastic and adaptable, rather than unchanging. To further clarify the underlying mechanisms, it is essential to identify the specific genes and signaling pathways that exert a decisive influence on the histological transformation in lung cancer. Additionally, understanding how these key elements interact with other signaling pathways to collectively drive the process of histological transformation is of paramount importance.
