Mohamed Reda Keddar

Translational studies of acquired immune checkpoint blockade (ICB) resistance focused so far on non-small cell lung cancer or melanoma, highlighting genetic defects in antigen presentation, chronic interferon signaling, or upregulation of alternative immune checkpoints as mechanisms of acquired resistance. We provide the largest and first pan-cancer comparison of acquired versus primary ICB resistance, expanding resistance characterization to understudied indications.

Keywords lung cancer NSCLC STK11 LKB1 KEAP1 DDR ATR inhibition ceralasertib immunotherapy Introduction KEAP1 is the third most commonly mutated tumor suppressor in lung adenocarcinoma (LUAD), and alterations in this gene commonly co-occur with KRAS activating mutations,1 the most prevalent oncogenic driver event in LUAD.2 KEAP1 is a negative regulator of NRF2, a master transcription factor that regulates anti-oxidative stress response.3 Thus, inactivating mutations in KEAP1 or activating...

Abstract Immune checkpoint blockade (ICB) has revolutionised cancer therapy, yet resistance - both primary and acquired - remains a significant obstacle, affecting the majority of patients. Here, we leveraged a large-scale, real-world clinicogenomic dataset to systematically explore the molecular underpinnings of ICB resistance in the post-progression setting.