The Hippo effector YAP regulates the response of cancer cells to MAPK pathway inhibitors

Bivona, Trever G.

doi:10.1080/23723556.2015.1021441

Cited by 32 publications

(28 citation statements)

References 9 publications

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“…These data are consistent with reports from the functional genomic screens that demonstrated that targeting CRAF could sensitize response to MEK inhibitors in KRAS-mutant tumors (10,13). In addition to targeting multiple signaling nodes within the MAPK pathway to maximize both level and duration of signaling inhibition, combining RAF709 with inhibitors targeting the upstream RTK activation such as EGFR (34,35), bypass mechanisms such as YAP1 (36) or targeting prosurvival BCL2 family members (37), may further enhance efficacy and reduce the development of drug resistance.…”

Section: Discussionsupporting

confidence: 89%

Antitumor Properties of RAF709, a Highly Selective and Potent Inhibitor of RAF Kinase Dimers, in Tumors Driven by Mutant RAS or BRAF

Shao¹,

Mishina²,

Feng³

et al. 2018

Cancer Research

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Resistance to the RAF inhibitor vemurafenib arises commonly in melanomas driven by the activated BRAF oncogene. Here, we report antitumor properties of RAF709, a novel ATP-competitive kinase inhibitor with high potency and selectivity against RAF kinases. RAF709 exhibited a mode of RAF inhibition distinct from RAF monomer inhibitors such as vemurafenib, showing equal activity against both RAF monomers and dimers. As a result, RAF709 inhibited MAPK signaling activity in tumor models harboring either BRAF alterations or mutant N- and KRAS-driven signaling, with minimal paradoxical activation of wild-type RAF. In cell lines and murine xenograft models, RAF709 demonstrated selective antitumor activity in tumor cells harboring BRAF or RAS mutations compared with cells with wild-type BRAF and RAS genes. RAF709 demonstrated a direct pharmacokinetic/pharmacodynamic relationship in tumor models harboring KRAS mutation. Furthermore, RAF709 elicited regression of primary human tumor-derived xenograft models with BRAF, NRAS, or KRAS mutations with excellent tolerability. Our results support further development of inhibitors like RAF709, which represents a next-generation RAF inhibitor with unique biochemical and cellular properties that enables antitumor activities in RAS-mutant tumors. In an effort to develop RAF inhibitors with the appropriate pharmacological properties to treat RAS mutant tumors, RAF709, a compound with potency, selectivity, and properties, was developed that will allow preclinical therapeutic hypothesis testing, but also provide an excellent probe to further unravel the complexities of RAF kinase signaling..

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Section: Discussionsupporting

confidence: 89%

Antitumor Properties of RAF709, a Highly Selective and Potent Inhibitor of RAF Kinase Dimers, in Tumors Driven by Mutant RAS or BRAF

Shao¹,

Mishina²,

Feng³

et al. 2018

Cancer Research

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“…45,46 A more complete understanding should involve these segments, as well as a mechanistic structural grasp of how MST activates the Hippo pathway and exactly how the Hippo pathway and YAP1 can rescue Ras and MAPK inhibition. Mutations in YAP1 are frequently observed in Ras-driven cancers, 10,11,14,47,48 and more. 15,16 RASSF5 tumor suppressor is currently among the key drug targets in Ras-related cancers due to its role in linking Ras/MAPK and YAP1.…”

Section: Resultsmentioning

confidence: 99%

The dynamic mechanism of RASSF5 and MST kinase activation by Ras

Liao

Jang

Tsai

et al. 2017

Phys. Chem. Chem. Phys.

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As a tumor suppressor, RASSF5 (NORE1A) activates MST1/2 thereby modulating the Hippo pathway. Structurally, activation involves RASSF5 and MST1/2 swapping their SARAH domains to form a SARAH heterodimer. This exposes the MST1/2 kinase domain which homodimerizes, leading to trans-autophosphorylation. The SARAH-SARAH interaction shifts RASSF5 away from its autoinhibited state and relieves MST1/2 autoinhibition. Separate crystal structures are available for the RA (Ras association) domain and SARAH dimer, where SARAH is a long straight α-helix. Using all-atom molecular dynamics simulations, we modeled the RASSF5 RA with a covalently connected SARAH to elucidate the dynamic mechanism of how SARAH mediates between autoinhibition and Ras triggered-activation. Our results show that in inactive RASSF5 the RA domain retains SARAH, yielding a self-associated conformation in which SARAH is in a kinked α-helical motif that increases the binding interface. When RASSF5 binds K-Ras4B-GTP, the equilibrium shifts toward SARAH’s interacting with MST. Since the RA/SARAH affinity is relatively low, whereas that of the SARAH heterodimer is in the nM range, we suggest that RASSF5 exerts its tumor suppressor action through competition with other Ras effectors for Ras effector binding site, as well as coincidentally its recruitment to the membrane to help MST activation. Thus, SARAH plays a key role in RASSF5’s tumor suppression action by linking the two major pathways in tumor cell proliferation: Ras and the MAPK (tumor cell proliferation-promoting) pathway, and the Hippo (tumor cell proliferation-suppressing) pathway.

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“…We examined the molecular signaling cascades underlying the anti-proliferative and pro-apoptotic activities of AgGom-and HiGom-treated MM96L. We focused our investigations on the Hippo, AKT, mTOR and MAPK signalling pathways that have been described to mediate proliferation in melanoma cells [19][20][21] . The Hippo pathway regulates cell proliferation and controls organ size and growth by cytosolic sequestration and inhibition of the pro-proliferative activity of Yes-associated protein (YAP), via phosphorylation of YAP at Ser127 (P-YAP Ser127 ).…”

Section: Gomesin Peptides Compromise the Viability Of Braf Mutated-mementioning

confidence: 99%

“…This is the first study to provide mechanistic details of how the arachnid-derived gomesin peptides, initially characterized as having antimicrobial, antifungal and anthelmintic activities, exhibit antiproliferative properties against human melanoma. We studied signaling cascades known to drive proliferation of melanoma cells, including the Hippo, AKT and MAPK pathways [19][20][21] .…”

Section: Gomesin Kills Melanoma Cells By Induction Of Late Apoptosismentioning

confidence: 99%

Gomesin inhibits melanoma growth by manipulating key signaling cascades that control cell death and proliferation

Ikonomopoulou

Pineda

Sainz

et al. 2019

Toxicon

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Consistent with their diverse pharmacology, peptides derived from venomous animals have been developed as drugs to treat disorders as diverse as hypertension, diabetes and chronic pain. Melanoma has a poor prognosis due in part to its metastatic capacity, warranting further development of novel targeted therapies. This prompted us to examine the anti-melanoma activity of the spider peptides gomesin (AgGom) and a gomesin-like homolog (HiGom). AgGom and HiGom dose-dependently reduced the viability and proliferation of melanoma cells whereas it had no deleterious effects on nontransformed neonatal foreskin fibroblasts. Concordantly, gomesin-treated melanoma cells showed a reduced G0/G1 cell population. AgGom and HiGom compromised proliferation of melanoma cells via activation of the p53/p21 cell cycle checkpoint axis and the Hippo signaling cascade, together with attenuation of the MAP kinase pathway. We show that both gomesin peptides exhibit antitumoral activity in melanoma AVATAR-zebrafish xenograft tumors and that HiGom also reduces tumour progression in a melanoma xenograft mouse model. Taken together, our data highlight the potential of gomesin for development as a novel melanoma-targeted therapy. Arthropods are the most abundant and widely distributed group of animals on earth. Within this group, spiders are one of the most speciose taxa, with over 47,000 species described to date 1. Over a period of more than 400 million years 2 , spiders have evolved a myriad of venom peptides that are used for prey capture and/or defense against predators, as well as hemocyte-derived host-defense peptides that play a key role in innate immunity 3. According to the ArachnoServer database 4 , more than 40 antimicrobial peptides have been isolated from spider venoms. Despite their sequence diversity, all of these peptides are small (1.9-8.6 kDa) and highly cationic (pI 9.7-11.8). Moreover, in striking contrast with venom-derived peptide neurotoxins, all but four of these antimicrobial peptides are devoid of disulfide bonds. They are typically amphipathic and broadly cytolytic. They appear to be structurally disordered in aqueous solution but adopt an α-helical conformation in the presence of phospholipid membranes 5. From an evolutionary perspective, it is striking that the vast majority of these antimicrobial peptides (39 in total) were isolated from the venoms of araneomorph ("modern") spiders. The three exceptions are disulfide-rich neurotoxic peptides isolated from venom of the Chilean rose tarantula Grammostola

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The Hippo effector YAP regulates the response of cancer cells to MAPK pathway inhibitors

Cited by 32 publications

References 9 publications

Antitumor Properties of RAF709, a Highly Selective and Potent Inhibitor of RAF Kinase Dimers, in Tumors Driven by Mutant RAS or BRAF

Antitumor Properties of RAF709, a Highly Selective and Potent Inhibitor of RAF Kinase Dimers, in Tumors Driven by Mutant RAS or BRAF

The dynamic mechanism of RASSF5 and MST kinase activation by Ras

Gomesin inhibits melanoma growth by manipulating key signaling cascades that control cell death and proliferation

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