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Heterogeneous and dynamic response of esophageal cancer to CDK4/6 inhibition

par Moresi, Fabiana
Président du jury Dewachter, Laurence
Promoteur Bisteau, Xavier
Co-Promoteur Beck, Benjamin
Publication Non publié, 2025-12-19

Thèse de doctorat

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Résumé :

Esophageal squamous cell carcinoma (eSCC) is a highly aggressive malignancy with poor clinical outcomes and limited therapeutic options. The current treatment paradigm, consisting of surgery combined with genotoxic chemotherapy, offers only marginal improvements in survival. While immune checkpoint inhibitors (ICIs) such as nivolumab and pembrolizumab have been reported to provide clinical benefits in a subset of patients with high PD-L1 expression, the majority of eSCC tumors remain immunologically "cold," consequently barely responsive or unresponsive to ICI-based therapy.Among the most frequently dysregulated oncogenic pathways in eSCC, the cyclin D–CDK4/6–Rb axis is mainly altered because by CCND1 amplification and CDKN2A inactivation. Despite the widespread use of CDK4/6 inhibitors in HR+/HER2- breast cancer, their evaluation in eSCC has been limited to second-line settings with modest efficacy, likely underestimated due to prior cytotoxic therapy and a lack of patient stratification. Recent preclinical studies suggest that CDK4/6 inhibition may exert immunomodulatory effects in addition to its cytostatic activity, but these have yet to be explored systematically in treatment-naïve eSCC.This study addresses this gap by investigating the effects of the CDK4/6 inhibitor palbociclib in a panel of 22 eSCC cell lines using an integrative multi-omics and phenotypic approach. Three distinct patterns of response, resistant, delayed, and arrested, were defined and found to correlate with RB1 pathway integrity. Notably, delayed responders displayed replication stress, micronuclei formation, activation of cytosolic DNA sensing and interferon signaling pathways. These changes were linked to an enhanced immune infiltration in a vascularized 3D microfluidic co-culture system, supporting the idea that CDK4/6 inhibition can prime the tumor microenvironment for immune engagement.Together, these findings nominate CDK4/6 inhibition not only as a potential first-line therapeutic strategy in molecularly defined eSCC, but also as an approach capable of modulating the immune landscape in a subset of tumors previously considered immunologically inert.