Hippo pathway mediates resistance to cytotoxic drugs

Gujral, Taranjit S.; Kirschner, Marc W.

doi:10.1073/pnas.1703096114

Cited by 70 publications

(61 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Cells were maintained in Doxycycline unless otherwise specified. YAPsh and control constructs were generously provided by Taran Gujral (Gujral and Kirschner, 2017). After transfection and antibiotic selection for two weeks, isolated single colonies were observed and were individually isolated.…”

Section: Author Contributionsmentioning

confidence: 99%

YAP independently regulates cell size and population growth dynamics via non-cell autonomous mediators

Mugahid

Kalocsay

Gruver

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

The Hippo pathway, in which changes at the cell surface and in the extracellular environment control the activity of a downstream transcription factor, known as YAP in mammalian cells and Yorkie in Drosophila, has recently taken center-stage as perhaps the most important pathway in metazoans for controlling organ size. In intact tissues YAP activity is inhibited and the organ does not overgrow. When the organ is damaged, YAP is active and necessary for growth and regeneration to occur. The exact process by which YAP drives organ and tissue growth is not fully understood, although it is known to affect both cell size and cell number. Since cell size and proliferation are highly interdependent in many cultured cell studies, we investigated the role of YAP in the simultaneous regulation of both cell size and number. Our experiments reveal that YAP controls both cell size and cell proliferation by independent circuits, and that it affects each process non-cell autonomously via extracellular mediators. We identify that CYR61, a known secreted YAP target, is the major regulator of the non-cell autonomous increase in cell number, but does not affect cell size. The molecular identity of the non-cell autonomously acting mediator of cell size is yet to be identified.

show abstract

Section: Author Contributionsmentioning

confidence: 99%

YAP independently regulates cell size and population growth dynamics via non-cell autonomous mediators

Mugahid

Kalocsay

Gruver

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…It is well established that dysregulated Hippo signaling promotes malignancy in cancer cells [29, 30]. Recently, Hippo signaling has also been correlated to mediate chemoresistance in different neoplasms to several chemotherapeutic drugs [31]. Similarly, phosphorylation at S397 of YAP-1 by LATS1/2 creates a phospho□degron motif for β□TrCP binding followed by proteasomal degradation [13].…”

Section: Discussionmentioning

confidence: 99%

RRBP1 rewires cisplatin resistance in Oral Squamous Cell Carcinoma by regulating YAP-1

Shriwas

Arya

Mohanty

et al. 2020

Preprint

View full text Add to dashboard Cite

30Cisplatin-based chemotherapy still remains as one of the primary treatment modalities for 31 OSCC. Several OSCC patients experience relapse owing to development of chemoresistance. To 32 identify key resistance triggering molecules, we performed global proteomic profiling of human 33 OSCC lines presenting with sensitive, early and late cisplatin resistance patterns. From the 34 proteomic profiling study, human RRBP1 was identified to be upregulated in both early and late 35 cisplatin-resistant cells with respect to the sensitive counterpart. Analysis of OSCC patient 36 sample indicates that RRBP1 expression is elevated in chemotherapy-non-responder tumors as 37 compared to chemotherapy-naïve tumors. Knocking out RRBP1 resulted in restoring cisplatin 38 mediated cell death in chemoresistant lines and patient derived cells (PDC). Mechanistically, 39 RRBP1 regulates YAP-1 to induce chemoresistance in OSCC. The chemoresistant PDC 40 xenograft data suggests that knock out of RRBP1 induces cisplatin mediated cell death and 41 facilitates a significant reduction of tumor burden. We also found Radezolid, a novel 42 oxazolidinone antibiotic represses the expression of RRBP1 and restores cisplatin-induced cell 43 death in chemoresistant OSCC. This unique combinatorial approach needs further clinical 44 investigation to target advanced OSCC. Here with for the first time, we uncover the novel role of 45 RRBP1 as potential modulator of cisplatin resistance in advanced OSCC.46 48 developing countries. OSCC is an aggressive form of HNSCC and is the most common cancer 49 among Indian males [1]. Approximately 80,000 new OSCC cases are reported annually with a 50 mortality of 46,000 individuals each year in India. The traditional treatment modalities for 51 advanced OSCC comprises of surgical removal of primary tumors followed by concomitant 52 adjuvant chemoradiotherapy [2]. In addition, neoadjuvant chemotherapy is frequently 53 recommended for surgically unresectable OSCC tumors that reduces tumor and provides more 54 surgical options. Despite having these solutions, the 5-year survival rate of advance tongue 55 OSCC is approximately 50%, indicating a possible resistance to currently available therapeutics. 56 Chemoresistance is one of the important factors for treatment failure in OSCC [3]. Cisplatin 57 alone or in combination with 5-fluorouracil and taxane/docetaxel (TPF) are generally used as 58 chemotherapy regimen for OSCC [4]. But due to chemoresistance development, patients 59 experience relapse which leads to continued tumor growth and metastasis. The chemoresistant 60properties could be attributed to enhanced cancer stem cell population, decreased drug 61 accumulation, reduced drug-target interaction, reduced apoptotic response and enhanced 62 autophagic activities [5]. These hallmarks present the endpoint events, when cancer cell had 63 already acquired chemoresistance. Till date, the causative factors responsible for acquiring 64 chemoresistance in cells are yet not explored. Identifying these molecular triggers ...

show abstract

“…The Hippo signaling pathway is one of the 10 oncogenic signaling pathways with frequent genetic alterations, and Hippo pathway genes such as LATS1/2 and YAP were somatically mutated in 10% of 9,125 tumors across 33 cancers profiled by The Cancer Genome Atlas (Sanchez‐Vega et al , ). YAP has recently been recognized as a key determinant that mediates drug resistance by acting in parallel to other signaling pathways (Lin et al , ; Gujral & Kirschner, ; Lee et al , ). Of note, overexpression of YAP and its target gene signatures has been reported to be associated with poor clinical outcomes in NSCLC patients (Wang et al , ).…”

Section: Discussionmentioning

confidence: 99%

“…YAP has emerged as a critical oncogene in multiple cancer types (Zanconato et al , ; Maugeri‐Saccà & De Maria, ). In particular, YAP has been reported to be closely associated with the emergence of resistance to conventional chemotherapeutics (Gujral & Kirschner, ) and BRAF/MEK/EGFR‐targeted therapies (Lin et al , ; Lee et al , ). However, only a few studies have verified the clinical relevance of YAP activation in human samples.…”

Section: Introductionmentioning

confidence: 99%

Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK ‐rearranged lung cancer

et al. 2019

View full text Add to dashboard Cite

Clinical benefit of ALK tyrosine kinase inhibitors (ALK‐TKIs) in ALK‐rearranged lung cancer has been limited by the inevitable development of acquired resistance, and bypass‐molecular resistance mechanisms remain poorly understood. We investigated a novel therapeutic target through screening FDA‐approved drugs in ALK‐TKI‐resistant models. Cerivastatin, the rate‐limiting enzyme inhibitor of the mevalonate pathway, showed anti‐cancer activity against ALK‐TKI resistance in vitro/in vivo, accompanied by cytoplasmic retention and subsequent inactivation of transcriptional co‐regulator YAP. The marked induction of YAP‐targeted oncogenes (EGFR, AXL, CYR61, and TGFβR2) in resistant cells was abolished by cerivastatin. YAP silencing suppressed tumor growth in resistant cells, patient‐derived xenografts, and EML4‐ALK transgenic mice, whereas YAP overexpression decreased the responsiveness of parental cells to ALK inhibitor. In matched patient samples before/after ALK inhibitor treatment, nuclear accumulation of YAP was mainly detected in post‐treatment samples. High expression of YAP in pretreatment samples was correlated with poor response to ALK‐TKIs. Our findings highlight a crucial role of YAP in ALK‐TKI resistance and provide a rationale for targeting YAP as a potential treatment option for ALK‐rearranged patients with acquired resistance to ALK inhibitors.

show abstract

Hippo pathway mediates resistance to cytotoxic drugs

Cited by 70 publications

References 66 publications

YAP independently regulates cell size and population growth dynamics via non-cell autonomous mediators

YAP independently regulates cell size and population growth dynamics via non-cell autonomous mediators

RRBP1 rewires cisplatin resistance in Oral Squamous Cell Carcinoma by regulating YAP-1

Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK ‐rearranged lung cancer

Contact Info

Product

Resources

About