CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation

Neuroendocrine(NE)transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor prognosis.Up to date,even if patients at high risk of transformation can be identified by the occurrence of Tumor Protein P53(TP53)and Retinoblastoma Transcriptional Corepressor 1(RB1)mutations in their tumors,no therapeutic strategies are available to prevent or delay histological transformation.Upregulation of the cell cycle kinase Cell Division Cycle 7(CDC7)occurred in tumors during the initial steps of NE transformation,already after TP53/RB1 co-inactivation,leading to induced sensitivity to the CDC7 inhibitor simurosertib.CDC7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of the MYC Proto-Oncogen(MYC),implicated in stemness and histological transformation.Ectopic overexpression of a degradation-resistant MYC isoform reestablished the NE transformation phenotype observed on targeted therapy,even in the presence of simurosertib.CDC7 inhibition also markedly extended response to standard cytotoxics(cisplatin,irinotecan)in lung and prostate small cell carcinoma models.These results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity,as well as to effectively treat NE tumors de novo or after transformation.As simurosertib clinical efficacy trials are ongoing,this concept could be readily translated for patients at risk oftransformation.

Tumor-intrinsic metabolic reprogramming and how it drives resistance to anti-PD-1/PD-L1 treatment

The development of immune checkpoint blockade (ICB) therapies has been instrumental in advancing the field of immunotherapy. Despite the prominence of these treatments, many patients exhibit primary or acquired resistance, rendering them ineffective. For example, anti-programmed cell death protein 1 (anti-PD-1)/anti-programmed cell death ligand 1 (anti-PD-L1) treatments are widely utilized across a range of cancer indications, but the response rate is only 10%-30%. As such, it is necessary for researchers to identify targets and develop drugs that can be used in combination with existing ICB therapies to overcome resistance. The intersection of cancer, metabolism, and the immune system has gained considerable traction in recent years as a way to comprehensively study the mechanisms that drive oncogenesis, immune evasion, and immunotherapy resistance. As a result, new research is continuously emerging in support of targeting metabolic pathways as an adjuvant to ICB to boost patient response and overcome resistance. Due to the plethora of studies in recent years highlighting this notion, this review will integrate the relevant articles that demonstrate how tumor-derived alterations in energy, amino acid, and lipid metabolism dysregulate anti-tumor immune responses and drive resistance to anti-PD-1/PD-L1 therapy.