Syndecan 4-c-ros Oncogene 1 Fusion as a Mechanism of Acquired Resistance in Epidermal Growth Factor Receptor Mutant Lung Adenocarcinoma
Introduction
Lung adenocarcinoma (LADC) driven by epidermal growth factor receptor (EGFR) mutations represents a significant subset of non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, have revolutionized treatment for patients harboring activating EGFR mutations, including exon 19 deletions and the exon 21 L858R point mutation. However, acquired resistance to EGFR-TKIs remains a major clinical challenge. While mechanisms such as the EGFR T790M mutation, HER2 amplification, and mesenchymal-epithelial transition (MET) amplification are well-documented, novel resistance pathways continue to emerge. This case report highlights the identification of a Syndecan 4-ROS1 (SDC4-ROS1) gene rearrangement as a potential mechanism of acquired resistance to EGFR-TKIs in a patient with EGFR-mutant LADC.
Clinical Case Presentation
A 37-year-old Chinese female, a non-smoker, presented in December 2014 with stage IV LADC involving the left lung, malignant pleural effusion, and multiple bone metastases (Figure 1A). Initial molecular profiling of the tumor biopsy revealed an EGFR exon 19 deletion, prompting first-line therapy with gefitinib. The patient achieved stable disease (SD) with only grade 1 rash as a side effect. However, disease progression occurred after two months, marked by the emergence of a small intracranial lesion and extracranial metastases. Subsequent management included whole-brain radiotherapy (30 Gy in ten fractions) and four cycles of pemetrexed monotherapy, followed by two cycles of pemetrexed combined with cisplatin, which yielded a partial response (PR). Maintenance therapy with pemetrexed was continued for 14 cycles, sustaining disease stability for 23 months until March 2017, when progression was noted in the left lung lesion and pleural effusion (Figure 1B).
Rebiopsy and next-generation sequencing (NGS) analysis at progression identified an SDC4-ROS1 fusion (Figure 1C), with no evidence of common resistance mechanisms like T790M or MET amplification. The patient was switched to crizotinib, a ROS1 inhibitor, in April 2017, achieving a PR with resolution of pleural effusion (Figure 1D). By August 2018, however, progression recurred in the left lung, necessitating further therapeutic adjustments.
Molecular Basis of EGFR-TKI Resistance
EGFR mutations in NSCLC predominantly localize to exons 18–21, with exon 19 deletions and L858R accounting for approximately 90% of cases. EGFR-TKIs inhibit constitutive kinase activity in these mutants, but resistance arises through secondary genetic alterations. The absence of T790M or other canonical resistance mechanisms in this case prompted exploration of alternative pathways.
ROS1 Rearrangements in NSCLC
The ROS1 proto-oncogene, encoding a receptor tyrosine kinase, was first implicated in oncogenesis through its viral homolog in avian sarcomas. ROS1 rearrangements drive dimerization and constitutive kinase activation, stimulating downstream oncogenic pathways such as PI3K/AKT/mTOR, STAT3, RAS/MAPK/ERK, and SHP1/2. In NSCLC, ROS1 fusions are identified in 1–2% of cases, predominantly in young, non-smoking females. Since the discovery of the first ROS1 fusion (CD74-ROS1) in 2007, 52 distinct ROS1 rearrangements have been reported. CD74 remains the most frequent partner (42% of cases), while SDC4-ROS1 is rare.
SDC4-ROS1 Fusion as a Resistance Mechanism
The SDC4-ROS1 fusion detected in this patient involves juxtaposition of the SDC4 promoter region with the ROS1 kinase domain, leading to ROS1 overexpression and ligand-independent signaling. This rearrangement was absent in the baseline tumor sample, confirming its acquisition during EGFR-TKI therapy. The temporal association between gefitinib resistance and SDC4-ROS1 emergence suggests a direct role in bypassing EGFR dependency.
Therapeutic Implications of ROS1 Inhibition
ROS1-driven tumors exhibit sensitivity to TKIs like crizotinib, which inhibits ROS1, ALK, and MET kinases. In this case, crizotinib induced a PR lasting 16 months, underscoring the clinical relevance of ROS1 targeting post-EGFR-TKI resistance. However, subsequent progression highlights the need for combinatorial strategies or next-generation ROS1 inhibitors to overcome resistance.
Co-occurrence of Driver Alterations in NSCLC
While concurrent driver mutations in NSCLC are rare, emerging reports describe co-existing EGFR, ROS1, ALK, or KRAS alterations. For instance, Zeng et al. documented a GOPC-ROS1 fusion arising after resistance to first- and third-generation EGFR-TKIs, with crizotinib/osimertinib combination therapy eliciting a response. Similarly, Zhu et al. reported a case with concurrent EGFR L858R and CD74-ROS1, though EGFR-TKI response was untested. These findings suggest that ROS1 rearrangements may arise under selective pressure from EGFR inhibition, necessitating rebiopsy and broad molecular profiling at progression.
Mechanistic Insights and Future Directions
The SDC4-ROS1 fusion exemplifies tumor plasticity in evading targeted therapies. Preclinical models suggest that EGFR inhibition may foster genomic instability or clonal selection of pre-existing ROS1-rearranged subpopulations. Alternatively, ROS1 activation may compensate for suppressed EGFR signaling through parallel survival pathways. Further studies are needed to delineate the interplay between EGFR and ROS1 signaling and to identify biomarkers predicting ROS1-mediated resistance.
Conclusion
This case provides compelling evidence that SDC4-ROS1 rearrangements represent a novel mechanism of acquired resistance to EGFR-TKIs in EGFR-mutant LADC. The clinical efficacy of crizotinib in this context underscores the importance of comprehensive genomic profiling upon progression. Future research should explore optimal therapeutic combinations, such as EGFR/ROS1 dual inhibition, and investigate the prevalence of ROS1 fusions in larger cohorts of EGFR-TKI-resistant patients.
doi.org/10.1097/CM9.0000000000000555
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