Journal of Experimental & Clinical Cancer Research最新文献

Background: Pancreatic ductal adenocarcinoma (PDAC) is often driven by KRAS mutations, but inhibitors targeting the most frequent KRAS substitutions in PDAC are not yet approved in the clinic. We previously discovered that KRAS-mutant PDAC is sensitive to the combination of SHP2 and ERK inhibitors, recently investigated in the Phase I/Ib clinical trial NCT04916236. Lately, RAS(ON) multi-selective inhibitors have entered clinical development, representing a promise for mono or combination therapies in PDAC. However, resistance may arise even for combination therapies. Here, we aimed at anticipating mechanisms of resistance to SHP2 plus ERK or RAS(ON) multi-selective inhibitors.

Methods: We performed a genome-wide CRISPR-KO screening, followed by four follow-up focused screenings, leading to the identification of resistance mediators, which were further validated through functional genetic and pharmacological experiments, both in vitro and in vivo.

Results: Through unbiased CRISPR-based screenings, we identified mTOR and JUN hyperactivation as interconnected mechanisms that overcome MAPK suppression. Further investigation pointed at JUN as the most downstream resistance mediator, and indirect therapeutic target, using MAP2K4 inhibitors.

Conclusions: Alterations in the PI3K/AKT/mTOR and JUN pathways can induce resistance to multiple combinations of MAPK pathway inhibitors, and may serve as biomarkers for sensitivity/resistance in clinical trials exploring such combinations in KRAS-mutant PDAC.

Metastatic progression, driven by the dissemination of circulating tumor cells (CTCs) through the bloodstream, remains the leading cause of cancer-related death. A rare subset of CTCs, characterized by tumor-initiating properties and phenotypic plasticity, plays a pivotal role in the formation of distant metastases. The ability of these cells to survive in the circulation, evade the immune surveillance, and establish secondary tumors underscores their biological significance. However, CTC extreme rarity and heterogeneity pose major challenges for their in-depth functional characterization. Disseminated tumor cells (DTCs) are cells that have extravasated and persist in distant organ niches, often in a dormant state, and represent a complementary and equally critical component of metastatic progression. Their capacity to remain quiescent for prolonged periods before reactivation highlights the need to study both CTCs and DTCs to fully understand metastasis initiation and relapse. Recent advances in CTC isolation and culture have led to the development of patient-derived CTC lines and CTC-derived xenograft animal models, offering unprecedented opportunities to investigate metastatic seeding, therapeutic resistance and tumor evolution. CTC- and DTC-based models provide valuable insights into the biology of CTCs from different cancer types, revealing key molecular drivers of metastasis formation and potential therapeutic targets. In this review, we summarize the state-of-the-art methodologies for establishing CTC- and DTC-based models and evaluate their contribution to understand tumor progression and response to treatments. We discuss the current challenges in generating and maintaining these models, including the influence of hypoxic conditions, enrichment strategies, and culture medium optimization. Then, we highlight their potential applications in precision oncology, particularly for biomarker discovery and for preclinical drug testing.