Abstract 84P
Background
SCLC is characterized by extreme heterogeneity and aggressive metastatic potential, driven by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states. Understanding the mechanisms driving this plasticity is critical to developing effective therapeutic strategies.
Methods
Through spatially resolved transcriptomics and proteomics, we show that fibroblast growth factor receptor (FGFR) signaling within the TME promotes SCLC evolution toward a non-NE state.
Results
We identified that various components of tumor microenvironment (TME), specifically cancer-associated fibroblasts (CAFs), as a key driver of SCLC cell-state transitions. These observations from patient derived tumors were confirmed using in-vitro experiments performed on SCLC cell lines providing new therapeutic opportunities targeting SCLC plasticity. In-vitro inhibition of SCLC cell lines incubated in FGF rich medium, with clinical grade pan-FGFR inhibitor, led to reduction in overall adherent state (non-NE state), NOTCH signaling as well as c-MYC and REST protein expression that are associated with NE to non-NE transition and intratumoral heterogeneity. FGF-FGFR paracrine signaling between NE and Non-NE SCLC cells has been shown to enhance local invasion and distant metastases as well as aid in chemoresistance. Additionally, combination of FGFR inhibition with Immune checkpoint inhibitors (ICI) may be safe, effective and synergistic. We propose a phase 1/2 clinical trial investigating the combination of pan-FGFR inhibitor and ICI in patients with extensive-stage SCLC. We hypothesize that FGFR inhibition in addition to ICI can restrain NE plasticity and enhance anti-tumor responses in the maintenance setting following chemo-immunotherapy for extensive stage SCLC that respond to induction chemo-immunotherapy. The primary endpoints will be to evaluate the safety and efficacy of this combination in delaying disease progression.
Conclusions
Our findings underscore the importance of TME-derived FGFR signaling in SCLC's adaptive resistance mechanisms and suggest that inhibiting this axis may restrain SCLC neuroendocrine plasticity, presenting a promising strategy to improve outcomes for patients with this highly lethal disease.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
National Cancer Institute.
Disclosure
A. Thomas: Financial Interests, Personal, Funding: Prolynx, EMS Seorono, Gilead Science. All other authors have declared no conflicts of interest.