A focal adhesion kinase-YAP signaling axis drives drug tolerant persister cells and residual disease in lung cancer

Haderk, Franziska; Fernández-Méndez, Celia; Cech, Lauren; Yu, Johnny; Meraz, Ismail M.; Olivas, Victor; Rabago, Dora Barbosa; Kerr, D. Lucas; Gómez, Carlos; Allegakoen, David V.; Guan, Juan; Shah, Khyati N.; Herrington, Kari A.; Gbenedio, Oghenekevwe; Nanjo, Shigeki; Majidi, Mourad; Tamaki, Whitney; Rotow, Julia; McCoach, Caroline E.; Riess, Jonathan W.; Gutkind, J. Silvio; Tang, Tracy; Post, Leonard; Santisteban, Pilar; Goodarzi, Hani; Bandyopadhyay, Sourav; Kuo, Calvin J.; Roose, Jeroen P.; Wu, Wei; Blakely, Collin M.; Roth, Jack A.; Bivona, Trever G.

doi:10.1101/2021.10.23.465573

Cited by 12 publications

(15 citation statements)

References 61 publications

(99 reference statements)

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“…This is supported by studies implicating YAP activation in persister cells after EGFR TKI treatment 44 . We recently reported YAP-driven transcriptional adaptation as a functional mechanism of TKI drug tolerance 45 . In this study, we found in experiments in humanized mice that YAP reduced treatment sensitivity to osimertinib and enhanced an immunosuppressive tumor microenvironment supporting tumor growth.…”

Section: Discussionmentioning

confidence: 99%

3-Phosphoinositide-dependent kinase 1 drives acquired resistance to osimertinib

Meraz

Majidi

Fang

et al. 2021

Preprint

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Osimertinib sensitive and resistant NSCLC NCI-H1975 clones were used to model osimertinib acquired resistance in humanized mice and delineate potential resistance mechanisms. No new EGFR mutations or loss of the EGFR T790M mutation were found in resistant clones. Resistant tumors in humanized mice were initially partially responsive to osimertinib, then aggressive tumor regrowth occurred accompanied by an immunosuppressive tumor microenvironment. 3-phosphoinositide-dependent kinase 1 (PDK1) was identified as a potential driver of osimertinib acquired resistance, and its selective inhibition by BX795 and CRISPR gene knock out, sensitized resistant clones and a patient derived xenograft (PDX) with acquired resistance to osimertinib. PDK1 knock-out dysregulated PI3K/Akt/mTOR signaling, promoted cell cycle arrest at the G1 phase, and inhibited nuclear translocation of yes-associated protein (YAP). Higher expression of PDK1 was found in patients with progressive disease following osimertinib treatment. PDK1 is a central upstream regulator of two critical drug resistance pathways: PI3K/AKT/mTOR and YAP.

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Section: Discussionmentioning

confidence: 99%

3-Phosphoinositide-dependent kinase 1 drives acquired resistance to osimertinib

Meraz

Majidi

Fang

et al. 2021

Preprint

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“…Additionally, RNA-seq analyses from an EGFR L858R -harbouring PDX model of lung adenocarcinoma 38 treated with the EGFR inhibitor erlotinib (Extended Data Fig. 12f) or the EGFR inhibitor osimertinib 29 (Extended Data Fig. 12g) also revealed an increase in A3B mRNA levels and a trend towards decrease in UNG mRNA levels upon treatment.…”

Section: Main Textmentioning

confidence: 98%

“…10a). To confirm these transcriptional changes, an independent RNA-seq dataset was examined 29 , generated from EGFR-mutant PC9 cells treated with the EGFR TKI osimertinib for 9 days. These EGFR TKI-treated cells also displayed a significant upregulation of A3B and downregulation of UNG transcripts (Extended Data Fig.…”

Section: Main Textmentioning

confidence: 99%

Targeted cancer therapy induces APOBEC fuelling the evolution of drug resistance

Mayekar¹,

Caswell

Law

et al. 2020

Preprint

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Introductory paragraphThe clinical success of targeted cancer therapy is limited by drug resistance that renders cancers lethal in patients1-4. Human tumours can evolve therapy resistance by acquiring de novo genetic alterations and increased heterogeneity via mechanisms that remain incompletely understood1. Here, through parallel analysis of human clinical samples, tumour xenograft and cell line models and murine model systems, we uncover an unanticipated mechanism of therapy-induced adaptation that fuels the evolution of drug resistance. Targeted therapy directed against EGFR and ALK oncoproteins in lung cancer induced adaptations favoring apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC)-mediated genome mutagenesis. In human oncogenic EGFR-driven and ALK-driven lung cancers and preclinical models, EGFR or ALK inhibitor treatment induced the expression and DNA mutagenic activity of APOBEC3B via therapy-mediated activation of NF-κB signaling. Moreover, targeted therapy also mediated downregulation of certain DNA repair enzymes such as UNG2, which normally counteracts APOBEC-catalyzed DNA deamination events. In mutant EGFR-driven lung cancer mouse models, APOBEC3B was detrimental to tumour initiation and yet advantageous to tumour progression during EGFR targeted therapy, consistent with TRACERx data demonstrating subclonal enrichment of APOBEC-mediated mutagenesis. This study reveals how cancers adapt and drive genetic diversity in response to targeted therapy and identifies APOBEC deaminases as future targets for eliciting more durable clinical benefit to targeted cancer therapy.

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“…VT2 and other TEAD palmitoylation inhibitors have shown efficacy in blocking resistance development when used in combination with osimertinib in mouse models of non-small cell lung cancer. 76 , 77 …”

Section: Discussionmentioning

confidence: 99%

Inhibition of YAP/TAZ-driven TEAD activity prevents growth of NF2-null schwannoma and meningioma

Laraba

Guibert

Hewitt

et al. 2022

Brain

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Schwannoma tumours typically arise on the 8th cranial nerve and are mostly caused by loss of the tumour suppressor Merlin (NF2). There are no approved chemotherapies for these tumours and the surgical removal of the tumour carries a high risk of damage to the 8th or other close cranial nerve tissue. New treatments for schwannoma and other NF2-null tumours such as meningioma are urgently required. Using a combination of human primary tumour cells and mouse models of schwannoma, we have examined the role of the Hippo signalling pathway in driving tumour cell growth. Using both genetic ablation of the Hippo effectors YAP and TAZ as well as novel TEAD palmitoylation inhibitors, we show that Hippo signalling may be successfully targeted in vitro and in vivo to both block and, remarkably, regress schwannoma tumour growth. In particular, successful use of TEAD palmitoylation inhibitors in a pre-clinical mouse model of schwannoma points to their potential future clinical use. We also identify the cancer stem cell marker aldehyde dehydrogenase 1A1 (ALDH1A1) as a Hippo signalling target, driven by the TAZ protein in human and mouse NF2-null schwannoma cells, as well as in NF2-null meningioma cells, and examine the potential future role of this new target in halting schwannoma and meningioma tumour growth.

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A focal adhesion kinase-YAP signaling axis drives drug tolerant persister cells and residual disease in lung cancer

Cited by 12 publications

References 61 publications

3-Phosphoinositide-dependent kinase 1 drives acquired resistance to osimertinib

3-Phosphoinositide-dependent kinase 1 drives acquired resistance to osimertinib

Targeted cancer therapy induces APOBEC fuelling the evolution of drug resistance

Inhibition of YAP/TAZ-driven TEAD activity prevents growth of NF2-null schwannoma and meningioma

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