Hippo Signaling at the Hallmarks of Cancer and Drug Resistance

Abstract

Originally identified in Drosophila melanogaster in 1995, the Hippo signaling pathway plays a pivotal role in organ size control and tumor suppression by inhibiting proliferation and promoting apoptosis. Large tumor suppressors 1 and 2 (LATS1/2) directly phosphorylate the Yki orthologs YAP (yes-associated protein) and its paralog TAZ (also known as WW domain-containing transcription regulator 1 [WWTR1]), thereby inhibiting their nuclear localization and pairing with transcriptional coactivators TEAD1-4. Earnest efforts from many research laboratories have established the role of mis-regulated Hippo signaling in tumorigenesis, epithelial mesenchymal transition (EMT), oncogenic stemness, and, more recently, development of drug resistances. Hippo signaling components at the heart of oncogenic adaptations fuel the development of drug resistance in many cancers for targeted therapies including KRAS and EGFR mutants. The first U.S. food and drug administration (US FDA) approval of the imatinib tyrosine kinase inhibitor in 2001 paved the way for nearly 100 small-molecule anti-cancer drugs approved by the US FDA and the national medical products administration (NMPA). However, the low response rate and development of drug resistance have posed a major hurdle to improving the progression-free survival (PFS) and overall survival (OS) of cancer patients. Accumulating evidence has enabled scientists and clinicians to strategize the therapeutic approaches of targeting cancer cells and to navigate the development of drug resistance through the continuous monitoring of tumor evolution and oncogenic adaptations. In this review, we highlight the emerging aspects of Hippo signaling in cross-talk with other oncogenic drivers and how this information can be translated into combination therapy to target a broad range of aggressive tumors and the development of drug resistance.

Keywords: EGFR; KRAS; cancer; carcinogenesis; combination therapy; drug resistance; hippo signaling.

Figure 1

Chemical structure of key TEAD inhibitors: IAG933 and the inhibitor 6 bind to the surface of TEAD at interface 3. Majority of inhibitors are designed against the central hydrophobic pocket. Lead molecules IK-930, VT107, GNE-7883, SWTX-143, Flufenamic acid (FA), and MGH-CP1 are non-covalent binders. K-975, mCMY020, MYF-03-176, and MYF-03-69 are covalent inhibitors targeting conserved cysteine residues in the pocket.

Figure 2

Targeting adaptive resistance of KRAS G12C mutation: in mutant KRAS cancer cells, KRAS inhibitors trigger mis-localization of Scrib and nuclear localization of YAP. YAP/TAZ-TEAD signaling and MAPK reactivation fuel the process of adaptive resistance in the presence of KRAS G12Ci (left panel). The combination of small-molecule Pan-TEAD inhibitor impairs the YAP/TAZ-TEAD nuclear binding and expression of transcriptional target genes, limiting adaptive resistance to KRAS inhibitors. Created in BioRender.com (accessed on 27 February 2024).

Figure 3

Strategy to target tumors with mutant EGFR and the development of drug resistance: in NSCLC, various forms of EGFR mutations led to intrinsic and acquired resistance in response to a tyrosine kinase inhibitor treatment. YAP/TAZ-TEAD engages the EMT transcription factor SLUG to directly repress pro-apoptotic BMF, limiting drug-induced apoptosis (A). The combination therapy of MEK/TEAD inhibitors disrupts the process of tumor evolution and development of drug resistance (B). Note: this model also covers a broad range of other EGFR mutations including EGFR exon 20 insertions and exon 21 mutations. Created in BioRender.com (accessed on 27 February 2022).