Identification of lncRNAs associated with T cells as potentialbiomarkers and therapeutic targets in lung adenocarcinoma

Lung adenocarcinoma (LUAD) is the most common and deadliest subtype of lung cancer. To select moretargeted and effective treatments for individuals, further advances in classifying LUAD are urgently needed. Thenumber, type, and function of T cells in the tumor microenvironment (TME) determine the progression andtreatment response of LUAD. Long noncoding RNAs (lncRNAs), may regulate T cell differentiation, development,and activation. Thus, our aim was to identify T cell-related lncRNAs (T cell-Lncs) in LUAD and to investigatewhether T cell-Lncs could serve as potential stratifiers and therapeutic targets. Seven T cell-Lncs were identified tofurther establish the T cell-related lncRNA risk score (TRS) in LUAD. Low TRS individuals were characterized byrobust immune status, fewer genomic alterations, and remarkably longer survival than high TRS individuals. Theexcellent accuracy of TRS in predicting overall survival (OS) was validated in the TCGA-LUAD training cohort andthe GEO-LUAD validation cohort. Our data demonstrated the favorable predictive power of the TRS-basednomogram, which had important clinical significance in estimating the survival probability for individuals. Inaddition, individuals with low TRS could respond better to chemotherapy and immunotherapy than those with highTRS. LINC00525 was identified as a valuable study target, and the ability of LUAD to proliferate or invade wassignificantly attenuated by downregulation of LINC00525. In conclusion, the TRS established by T cell-Lncs couldunambiguously classify LUAD patients, predict their prognosis and guide their management. Moreover, our identifiedT cell-Lncs could provide potential therapeutic targets for LUAD.

Targeting cancer stem cells in drug discovery: Current state and future perspectives

In recent decades,cancer stem cells(CSCs)have been increasingly identified in many malignancies.CSC-related signaling pathways and their functions provide new strategies for treating cancer.The aberrant activation of related signaling pathways(e.g.,Wnt,Notch,and Hedgehog pathways)has been linked to multiple types of malignant tumors,which makes these pathways attractive targets for cancer therapy.CSCs display many characteristic features,such as self-renewal,differentiation,high tumorigenicity,and drug resistance.Therefore,there is an urgent need to develop new therapeutic strategies to target these pathways to control stem cell replication,survival,and differentiation.Notable crosstalk occurs among different signaling pathways and potentially leads to compensatory escape.Therefore,multitarget inhibitors will be one of the main methods to overcome the drug resistance of CSCs.Many small molecule inhibitors of components of signaling pathways in CSCs have entered clinical trials,and some inhibitors,such as vismodegib,sonidegib,and glasdegib,have been approved.Tumor cells are susceptible to sonidegib and vismodegib resistance due to mutations in the Smo protein.The signal transducers and activators of transcription 3(STAT3)inhibitor BBI608 is being evaluated in a phase III trial for a variety of cancers.Structural derivatives of BBI608 are the main focus of STAT3 inhibitor development,which is another strategy for CSC therapy.In addition to the potential pharmacological inhibitors targeting CSCrelated signaling pathways,other methods of targeting CSCs are available,such as nano-drug delivery systems,mitochondrion targeting,autophagy,hyperthermia,immunotherapy,and CSC microenvironment targeting.In addition,we summarize the latest advances in the clinical development of agents targeting CSC-related signaling pathways and other methods of targeting CSCs.