C10714028

(Cancer Cell 29, 297–310; March 14, 2016)

Kinase inhibitor resistance often involves upregulation of poorly understood "bypass" signaling pathways. Here, we show that extracellular proteomic adaptation is one path to bypass signaling and drug resistance. Proteolytic shedding of surface receptors, which can provide negative feedback on signaling activity, is blocked by kinase inhibitor treatment and enhances bypass signaling. In particular, MEK inhibition broadly decreases shedding of multiple receptor tyrosine kinases (RTK), including HER4, MET, and most prominently AXL, an ADAM10 and ADAM17 substrate, thus increasing surface RTK levels and mitogenic signaling. Progression-free survival of patients with melanoma treated with clinical BRAF/MEK inhibitors inversely correlates with RTK shedding reduction following treatment, as measured noninvasively in blood plasma. Disrupting protease inhibition by neutralizing TIMP1 improves MAPK inhibitor efficacy, and combined MAPK/AXL inhibition synergistically reduces tumor growth and metastasis in xenograft models. Altogether, extracellular proteomic rewiring through reduced RTK shedding represents a surprising mechanism for bypass signaling in cancer drug resistance.

Significance: Genetic, epigenetic, and gene expression alterations often fail to explain adaptive drug resistance in cancer. This work presents a novel post-translational mechanism of such resistance: Kinase inhibitors, particularly targeting MAPK signaling, increase tumor cell surface receptor levels due to widely reduced proteolysis, allowing tumor signaling to circumvent intended drug action. Cancer Discov; 6(4); 382–99. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 331

Fragile X syndrome, the most common form of inherited intellectual disability, is caused by loss of the fragile X mental retardation protein (FMRP). However, the mechanism remains unclear, and effective treatment is lacking. We show that loss of FMRP leads to activation of adult mouse neural stem cells (NSCs) and a subsequent reduction in the production of neurons. We identified the ubiquitin ligase mouse double minute 2 homolog (MDM2) as a target of FMRP. FMRP regulates Mdm2 mRNA stability, and loss of FMRP resulted in elevated MDM2 mRNA and protein. Further, we found that increased MDM2 expression led to reduced P53 expression in adult mouse NSCs, leading to alterations in NSC proliferation and differentiation. Treatment with Nutlin-3, a small molecule undergoing clinical trials for treating cancer, specifically inhibited the interaction of MDM2 with P53, and rescued neurogenic and cognitive deficits in FMRP-deficient mice. Our data reveal a potential regulatory role for FMRP in the balance between adult NSC activation and quiescence, and identify a potential new treatment for fragile X syndrome.

Nature Reviews Cancer 16, 251 (2016). doi:10.1038/nrc.2016.15

Authors: Giovanni Stracquadanio, Xuting Wang, Marsha D. Wallace, Anna M. Grawenda, Ping Zhang, Juliet Hewitt, Jorge Zeron-Medina, Francesc Castro-Giner, Ian P. Tomlinson, Colin R. Goding, Kamil J. Cygan, William G. Fairbrother, Laurent F. Thomas, Pål Sætrom, Federica Gemignani, Stefano Landi, Benjamin Schuster-Böckler, Douglas A. Bell & Gareth L. Bond

Decades of research have shown that mutations in the p53 stress response pathway affect the incidence of diverse cancers more than mutations in other pathways. However, most evidence is limited to somatic mutations and rare inherited mutations. Using newly abundant genomic data, we demonstrate that

Two recent studies evaluated a small molecule that specifically binds to and inactivates the KRAS G12C mutant. The new findings argue that the perception that mutant KRAS is persistently frozen in its active GTP-bound form may not be accurate.

Jing et al. develop a thiomyristoyl lysine compound, TM, as a potent SIRT2-specific inhibitor with broad anticancer activity but little effect on non-cancerous cells. SIRT2 inhibition promotes c-Myc ubiquitination and degradation, suggesting the therapeutic potential of TM to target certain c-Myc-driven cancers.

Foster et al. show that oncogenic in-frame deletions of BRAF, HER2, and EGFR restrain the C helix (αC) in a fixed “in” active conformation, resulting in resistance to commonly used αC “out” inhibitors, and that five amino acid deletion provides optimal kinase activation.

Nature Medicine 22, 232 (2016). doi:10.1038/nm.4058

Author: Geoffrey R Oxnard

Two new studies show that mechanisms of acquired resistance to targeted therapy in lung cancer do not necessarily pre-exist in resistant subclones. Instead, some cancers may harbor the potential to acquire a variety of drug-resistance mechanisms after response to targeted therapy.

Publication date: 1 February 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 3
Author(s): Robert J. Pasteris, Mary Ann Hanagan, John J. Bisaha, Bruce L. Finkelstein, Lisa E. Hoffman, Vann Gregory, John L. Andreassi, James A. Sweigard, Boris A. Klyashchitsky, Yewande T. Henry, Richard A. Berger
Oxathiapiprolin is the first member of a new class of piperidinyl thiazole isoxazoline fungicides with exceptional activity against plant diseases caused by oomycete pathogens. It acts via inhibition of a novel fungal target—an oxysterol binding protein—resulting in excellent preventative, curative and residual efficacy against key diseases of grapes, potatoes and vegetables. Oxathiapiprolin is being developed globally as DuPont™ Zorvec™ disease control with first registration and sales anticipated in 2015. The discovery, synthesis, optimization and biological efficacy are presented.

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Publication date: 1 February 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 3
Author(s): Yuanqiong Huang, Yongxian Liu, Yuxiu Liu, Hongjian Song, Qingmin Wang
According to our previous work and the latest research on the biosynthesis of β-carboline, and using the reverse thinking strategy, tryptophan, the biosynthesis precursor of β-carboline alkaloids, and their derivatives were synthesized, and their biological activities and structure–activity relationships were studied. This bioassay showed that these compounds exhibited good inhibitory activities against tobacco mosaic virus (TMV); especially (S)-2-amino-3-(1H-indol-3-yl)-N-octylpropanamide (4) (63.3±2.1%, 67.1±1.9%, 68.7±1.3%, and 64.5±3.1%, 500μg/mL) exhibited the best antiviral activity both in vitro and in vivo. Compound 4 was chosen for the field trials and the acute oral toxicity test, the results showed that the compound exhibited good anti-TMV activity in the field and low acute oral toxicity. We also found that these compounds showed antifungal activities and insecticidal activities.

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Publication date: 11 January 2016
Source:Cancer Cell, Volume 29, Issue 1
Author(s): Alice Soragni, Deanna M. Janzen, Lisa M. Johnson, Anne G. Lindgren, Anh Thai-Quynh Nguyen, Ekaterina Tiourin, Angela B. Soriaga, Jing Lu, Lin Jiang, Kym F. Faull, Matteo Pellegrini, Sanaz Memarzadeh, David S. Eisenberg
Half of all human cancers lose p53 function by missense mutations, with an unknown fraction of these containing p53 in a self-aggregated amyloid-like state. Here we show that a cell-penetrating peptide, ReACp53, designed to inhibit p53 amyloid formation, rescues p53 function in cancer cell lines and in organoids derived from high-grade serous ovarian carcinomas (HGSOC), an aggressive cancer characterized by ubiquitous p53 mutations. Rescued p53 behaves similarly to its wild-type counterpart in regulating target genes, reducing cell proliferation and increasing cell death. Intraperitoneal administration decreases tumor proliferation and shrinks xenografts in vivo. Our data show the effectiveness of targeting a specific aggregation defect of p53 and its potential applicability to HGSOCs.

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Using p53-mutant, high-grade, serous ovarian carcinoma as model systems, Soragni et al. show that a cell-penetrating peptide designed to inhibit p53 amyloid formation rescues p53 functions and reduces in vivo xenograft growth and metastasis.