In situ modeling of acquired resistance to RTK/RAS-pathway-targeted therapies

Small-cell lung cancer (SCLC) is designated a recalcitrant cancer due to its five-year relative survival rate of less than 7%. First line SCLC treatment has not changed in the last 40 years. The NeuroD1 subtype of SCLC (SCLC-N) commonly harbors MYC amplifications and other hallmarks of aggressive behavior. Finding novel therapeutic options that effectively eliminate residual disease observed after initial response to therapy is essential to improving SCLC patient outcome. Tumor-initiating cells (TICs) are reported as the sanctuary population within the bulk tumor responsible for therapeutic resistance and relapse. In contrast to earlier studies in which ERK activation is reported to be inhibitory to growth and tumor development, we show that KSR1 signaling is conserved in SCLC-N and that it regulates tumor initiation through ERK. Thus, KSR1 function in SCLC-N serves as a novel model for understanding the role of KSR1-dependent signaling in normal and malignant tissues. We further show that KSR1 mediates cisplatin resistance in SCLC-N cells. CRISPR/Cas9-mediated KSR1 knockout causes a dramatic increase in sensitivity to cisplatin and is coincident with a marked decrease in TICs, indicating that targeting KSR1 might be selectively toxic to cells responsible for therapeutic resistance and tumor initiation. Our data show that KSR1, a molecular scaffold for the Raf/MEK/ERK signaling cascade, is critical for tumor initiation and clonogenicity, bothin vitroandin vivoin the highly aggressive, metastatic and therapy resistant NeuroD1 subtype of SCLC. These findings shed light on a key distinct protein responsible for regulation in SCLC-N tumors, and a potential subtype specific therapeutic target.

show abstract

Mediating kinase activity in Ras-mutant cancer: potential for an individualised approach?

Healy,

Turner,

Marensi

et al. 2024

Front. Pharmacol.

View full text Add to dashboard Cite

It is widely acknowledged that there is a considerable number of oncogenic mutations within the Ras superfamily of small GTPases which are the driving force behind a multitude of cancers. Ras proteins mediate a plethora of kinase pathways, including the MAPK, PI3K, and Ral pathways. Since Ras was considered undruggable until recently, pharmacological targeting of pathways downstream of Ras has been attempted to varying success, though drug resistance has often proven an issue. Nuances between kinase pathway activation in the presence of various Ras mutants are thought to contribute to the resistance, however, the reasoning behind activation of different pathways in different Ras mutational contexts is yet to be fully elucidated. Indeed, such disparities often depend on cancer type and disease progression. However, we are in a revolutionary age of Ras mutant targeted therapy, with direct-targeting KRAS-G12C inhibitors revolutionising the field and achieving FDA-approval in recent years. However, these are only beneficial in a subset of patients. Approximately 90% of Ras-mutant cancers are not KRAS-G12C mutant, and therefore raises the question as to whether other distinct amino acid substitutions within Ras may one day be targetable in a similar manner, and indeed whether better understanding of the downstream pathways these various mutants activate could further improve therapy. Here, we discuss the favouring of kinase pathways across an array of Ras-mutant oncogenic contexts and assess recent advances in pharmacological targeting of various Ras mutants. Ultimately, we will examine the utility of individualised pharmacological approaches to Ras-mediated cancer.

show abstract

In situ modeling of acquired resistance to RTK/RAS-pathway-targeted therapies

Cited by 3 publications

References 54 publications

Protocol for modeling acquired resistance to targeted therapeutics in adherent and suspension cancer cell lines via in situ resistance assay

Protocol for modeling acquired resistance to targeted therapeutics in adherent and suspension cancer cell lines via in situ resistance assay

KSR1 regulates small-cell lung carcinoma tumor initiation and cisplatin resistance

Mediating kinase activity in Ras-mutant cancer: potential for an individualised approach?

Contact Info

Product

Resources

About