Targeting YAP/TAZ in Combination with PD-L1 Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer (NSCLC)

Abstract

The survival of non-small cell lung cancer (NSCLC) patients has improved in the last decade as a result of introducing new therapeutics, such as immune checkpoint inhibitors, in the clinic. Still, some NSCLC patients do not benefit from these therapies due to intrinsic resistance or the development of acquired resistance and their malignant disease progresses. Further research on the molecular underpinnings of NSCLC pathobiology is required in order to discover clinically relevant molecular targets that regulate tumor immunity and to develop reasonable therapeutic combinations that will promote the efficacy of immune checkpoint inhibitors. Yes-associated Protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), the final effectors of the Hippo signaling transduction pathway, are emerging as key players in NSCLC development and progression. Herein, we overview studies that have investigated the oncogenic role of YAP/TAZ in NSCLC, focusing on immune evasion, and highlight the therapeutic potential of combining YAP/TAZ inhibitory agents with immune checkpoint inhibitors for the management of NSCLC patients.

Searching for Novel Biomarkers in Thymic Epithelial Tumors: Immunohistochemical Evaluation of Hippo Pathway Components in a Cohort of Thymic Epithelial Tumors

“…On the other hand, in response to DNA damage, LATS1 is implicated in the regulation of G2/M transition by inactivating Polo-like kinase 1 (Plk1), a serine/threonine-protein kinase, that progresses the cell-cycle and entry into the mitotic phase. Another intriguing function of YAP and TAZ, of paramount translational/clinical interest and with profound implications in routine patient treatment, is the upregulation of PD-L1, which designates the eminent impact of YAP and TAZ in regulating tumor cell immunogenicity and has been recorded in heterogenous malignancies [43][44][45][46][47][48][49][50][51].…”

Advancing non-small cell lung cancer treatment: the power of combination immunotherapies

“…This strategy aimed to overcome resistance issues associated with current immunotherapies by targeting molecular pathways linked to NSCLC development. By inhibiting YAP/TAZ, researchers sought to modulate the immune response against NSCLC tumors, potentially amplifying the efficacy of ICIs ( 207 ). These findings indicate the persistent challenges in treating NSCLC despite advancements in ICIs.…”

Are YAP and TAZ valid prognostic signatures for NSCLC patients?

“…YAP and TAZ stimulate immunosuppression in NSCLC; therefore, they can be used in combination regimens with immune checkpoint inhibitors but also as predictive biomarkers in the context of immune checkpoint inhibition. 4 A collection of studies has evaluated the association of YAP/TAZ expression in NSCLC with clinical, pathological and survival parameters. In a comprehensive review and meta-analysis, the expression levels of YAP and TAZ and their role as prognostic markers were assessed in a total of 1977 patients across five studies with lung cancers.…”

“…YAP and TAZ stimulate immunosuppression in NSCLC; therefore, they can be used in combination regimens with immune checkpoint inhibitors but also as predictive biomarkers in the context of immune checkpoint inhibition. 4 …”