Biology subjects

Fradette, J. J.

Publications and source records attributed to Fradette, J. J..

2 recordsLinked to original sources

bioRxiv2025

PDK1 and YAP1/TEAD signaling drive acquired KRAS inhibitor resistance in KRAS-mutant non-small cell lung cancer.

Mutations in KRAS are responsible for driving approximately 30% of NSCLC. While historically considered undruggable, recent breakthroughs have seen the FDA approval of two potent KRASG12C inhibitors, sotorasib (AMG510) and adagrasib (MRTX849). However, the efficacy of these inhibitors in the clinics has been limited by primary and acquired means of resistance. To elucidate mechanisms of acquired resistance, we generated a panel of resistant cell lines to the allele-specific KRAS inhibitors MRTX849 and MRTX1133 and observed an increased activation of the PDK1 and YAP1/TEAD signaling pathways. Pharmacological inhibition and genetic loss-of-function studies revealed a strong dependence on these pathways for the generation and maintenance of resistance to KRAS inhibition, which was then validated in vitro and in vivo. Furthermore, overexpression studies revealed that forced expression of either PDK1 or YAP1 led to increased resistance to KRAS inhibition in the sensitive lines. Taken together, our findings suggest that co-targeting PDK1 or YAP1/TEAD might be a potential approach to overcoming resistance to KRAS inhibition in NSCLC.

cancer biology↗

bioRxiv2020

Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance in KRAS/p53 mutant lung cancers

Understanding resistance mechanisms to targeted therapies and immune checkpoint blockade in mutant KRAS lung cancers is critical to developing novel combination therapies and improving patient survival. Here, we show that MEK inhibition enhanced PD-L1 expression while PD-L1 blockade upregulated MAPK signaling in mutant KRAS lung tumors. Combined MEK inhibition with anti-PD-L1 synergistically reduced lung tumor growth and metastasis, but tumors eventually developed resistance to sustained combinatorial therapy. Multi-platform profiling revealed that resistant lung tumors have increased infiltration of Th17 cells, which secrete IL-17 and IL-22 cytokines to promote lung cancer cell invasiveness and MEK inhibitor resistance. Antibody depletion of IL-17A in combination with MEK inhibition and PD-L1 blockade markedly reduced therapy-resistance in vivo. Clinically, increased expression of Th17-associated genes in melanoma patients treated with PD-1 blockade predicted poorer overall survival and response. Our study validates a triple combinatorial therapeutic strategy to overcome resistance to combined MEK inhibitor and PD-L1 blockade.

cancer biology↗