The
oncogene encodes a tyrosine kinase (TK) receptor. Its activation protects cells from death but also stimulates DNA damage response by triggering excess replicative stress. Transcriptomic ...classification of cancer cell lines based on
expression showed that response to the PARP inhibitor (PARPi) olaparib is poorer in
overexpressing cell lines. Accordingly, a high
expressing lung carcinoma cell line was sensitized to PARPi by
TK inhibition. This was not linked solely to
overexpression: other
overexpressing cell lines were biochemically but not functionally responsive to combined inhibition. Moreover, exogenously induced
overexpression was unable to induce resistance to PARPi. The
overexpressing cell line, responsive to the combined PARP and
inhibition, carried a heterozygous mutation of the ATM gene and showed an attenuated response of ATM to PARPi. Among the downstream targets of ATM activation, NuMA was phosphorylated only in response to the combined PARP and
inhibition. Given the role played by NuMA in mitosis, data show that the latter is affected by
and PARP inhibition in cells with haploinsufficient ATM. This is important as ATM heterozygous mutation is frequently found in human cancer and in lung carcinomas in particular.
The hepatocyte growth factor (HGF) also known as scatter factor activates cancer cell invasion and metastasis. We show that in ovarian cancer cells HGF induced the phosphorylation of the small heat ...shock protein of 27 kDa (HSP27) by activating the p38MAPK. HSP27 is increased in many cancers at advanced stage including ovarian cancer and associated with cancer resistance to therapy and poor patients' survival. The phosphorylation of HSP27 regulates both its chaperone activity and its control of cytoskeletal stability. We show that HSP27 was necessary for the remodeling of actin filaments induced by HGF and that motility in vitro depended on the p38MAPK‐MK2 axis. In vivo, HSP27 silencing impaired the ability of the highly metastatic, HGF‐secreting ovarian cancer cells to give rise to spontaneous metastases. This was due to defective motility across the vessel wall and reduced growth. Indeed, HSP27 silencing impaired the ability of circulating ovarian cancer cells to home to the lungs and to form experimental hematogenous metastases and the capability of cancer cells to grow as subcutaneous xenografts. Moreover, HSP27 suppression resulted in the sensitization of xenografts to low doses of the chemotherapeutic paclitaxel, likely because HSP27 protected microtubules from bundling caused by the drug. Altogether, these data show that the HSP27 is required for the proinvasive and prometastatic activity of HGF and suggest that HSP27 might be not only a marker of progression of ovarian cancer, but also a suitable target for therapy.
What's new?
Hepatocyte growth factor, HGF, induces cancers to spread. Recently, researchers learned that it activates a small heat shock protein, HSP27, which is increased in advanced stage cancers, and associated with resistance to chemotherapy. In this paper, the authors showed that silencing HSP27 stopped ovarian cancer cells from metastasizing. Suppressing HSP27 also sensitized the tumors to Paclitaxel. The results show that HSP27 is important for metastasis and invasion, and could make a promising target for therapy.
Background
Copy-number alterations of chromosome 1q are frequently found in multiple myeloma (MM) and are associated with poor prognosis. Recently, it has been demonstrated that the number of 1q ...copies correlates with a high-risk behavior (BA Walker et al, Leukemia 2019, TM Schmidt et al, Blood Cancer J 2019), but no data are available in carfilzomib-treated patients (pts). Here we aim at dissecting the role of Gain1q (3 copies of 1q) vs amplification 1q (Amp1q, ≥4 copies of 1q) in carfilzomib-treated NDMM pts enrolled in the randomized FORTE trial (NCT02203643).
Methods
Fluorescence in situ hybridization (FISH) in CD138+ purified bone marrow plasma cells (BMPCs) was centralized and performed at baseline. Two hundred BMPC nuclei from each sample were scored. The cut-off level for Gain1q was 10% of nuclei with ≥3 copies of 1q (mean plus 3 standard deviations of 1q alterations in BMPC from 15 healthy donors). The cut-off for Amp1q was 20% of nuclei with ≥4 copies of 1q.
In the FORTE trial, transplant-eligible NDMM pts were randomized to receive carfilzomib (K) lenalidomide (R) dexamethasone (d) induction followed by autologous stem-cell transplantation (ASCT) and KRd consolidation (KRd_ASCT), 12 KRd cycles (KRd12) or K-cyclophosphamide(C)-d induction, followed by ASCT and KCd consolidation (KCd_ASCT). After consolidation, pts were further randomized to receive KR vs R maintenance.
Results
A total of 474 pts were enrolled. Median follow-up from 1st randomization was 45 months (m). Evaluation of 1q by FISH was missing in 70 pts (15%), while in 4 pts (1%) FISH was present but the number of 1q copies was not evaluable. Among evaluable pts, chromosome 1q was normal in 219 (55%) pts, Gain1q was found in 129 (32%) pts, while Amp1q in 52 (13%). Gain1q- and Amp1q-positive pts were well distributed among treatment arms.
Baseline characteristics associated with Amp1q, compared to Gain1q, were LDH >upper limit of normal (P=0.002) and low hemoglobin (P=0.029) and platelets (P=0.044).
Best response to therapy was not significantly different in Normal 1q vs Gain1q vs Amp1q groups (≥very good partial response rates: 85% vs 84% vs 77%; stringent complete response rates: 52% vs 50% vs 38%). Best overall minimal residual disease negativity by flow cytometry (sensitivity 10-5) pre-maintenance was also not significantly different (55% vs 55% vs 44%, respectively).
In a multivariate analysis adjusted for treatment and Revised International Staging System (R-ISS), the risk of progression/death was significantly higher in the presence of Gain1q vs Normal 1q (HR 1.65, 95% CI 1.14-2.37, P=0.007) and the highest in the presence of Amp1q as compared to both Normal 1q (HR 3.04, 95% CI 1.99-4.65, P<0.001) and Gain1q (HR 1.84, 95% CI 1.21-2.81, P=0.004; Fig. 1A).
Median progression-free-survival (PFS) was not reached in the Normal 1q group, while Gain1q (53 m) and especially Amp1q (21.8 m) groups performed very poorly.
The presence of Amp1q vs Normal 1q (HR 5.88, 95% CI 3.10-11.17, P<0.001) and Gain1q (HR 3.13, 95% CI 1.73-5.68, P<0.001) predicted a lower overall survival as well (Fig. 1B).
Subgroup analysis on the presence/absence of concomitant high-risk features was performed. Gain1q predicted a lower PFS compared to Normal 1q in the presence of concomitant standard-risk features (ISS 1, ISS 2, standard-risk cytogenetics) but not in the presence of high-risk disease (ISS 3, high-risk cytogenetics). On the other hand, the worse prognosis of Amp1q pts was confirmed across all subgroups.
A subgroup analysis according to the upfront treatment received was performed. Interestingly, treatment with KRd_ASCT completely abrogated the risk conferred by Gain1q (HR 1.25 vs Normal 1q, 95% CI 0.58-2.7, P=0.565), while Amp1q-positive pts still showed a very poor outcome (median PFS 17 m, HR 6.03 vs Normal 1q, 95% CI 2.78-13.1, P<0.001).
In KCd_ASCT and KRd12-treated pts, the 3 groups performed similarly to the overall population.
Conclusion
This is a first report on the prognostic role of the number of 1q copies in carfilzomib-treated NDMM pts. Having ≥4 copies of 1q universally predicts a very poor PFS and OS despite the use of a 2nd generation proteasome inhibitor upfront. On the other hand, KRd_ASCT completely abrogated the PFS disadvantage conferred by 3 copies of 1q.
RNA sequencing on representative samples of Normal 1q vs Gain1q vs Amp1q is in progress to explore differentially expressed genes in Amp1q pts that could be exploited in future treatment strategies.
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D'Agostino:GSK: Membership on an entity's Board of Directors or advisory committees. Giuliani:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Participation in congresses, Research Funding; Janssen Pharmaceutical: Membership on an entity's Board of Directors or advisory committees, Other: Clinical study sponsorship; participation in congresses, Research Funding; Millennium Pharmaceutical: Other: Clinical study sponsorship, Research Funding; GSK: Other: Clinical study sponsorship, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Other: Participation in congresses. Tacchetti:Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; AbbVie: Honoraria; Oncopeptides: Honoraria; Bristol-Myers Squibb: Honoraria. Musto:Amgen: Honoraria; Celgene: Honoraria. Boccadoro:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Gay:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees.
The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including carfilzomib, cyclophosphamide, lenalidomide and dexamethasone).
Anaplastic Large Cell Lymphoma (ALCL) is a subtype of non-Hodgkin lymphoma frequently driven by the chimeric tyrosine kinase NPM-ALK, generated by the t (2,5)(p23;q35) translocation. While ALK+ ALCL ...belongs to mature T cell lymphomas, loss of T cell identity is observed in the majority of ALCL secondary to a transcriptional and epigenetic repressive program induced by oncogenic NPM-ALK. While inhibiting the expression of T cell molecules, NPM-ALK activates surrogate TCR signaling by directly inducing pathways downstream the TCR. CD45 is a tyrosine phosphatase that plays a central role in T cell activation by controlling the TCR signaling and regulating the cytokine responses through the JAK/STAT pathway and exists in different isoforms depending on the stage of T-cell maturation, activation and differentiation. ALK+ ALCL cells mainly express the isoform CD45RO in keeping with their mature/memory T cell phenotype. Because of its regulatory effect on the JAK/STAT pathway that is essential for ALK+ ALCL, we investigated whether CD45 expression was affected by oncogenic ALK. We found that most ALK+ ALCL cell lines express the CD45RO isoform with modest CD45RA expression and that NPM-ALK regulated the expression of these CD45 isoforms. Regulation of CD45 expression was dependent on ALK kinase activity as CD45RO expression was increased when NPM-ALK kinase activity was inhibited by treatment with ALK tyrosine kinase inhibitors (TKIs). Silencing ALK expression through shRNA or degradation of ALK by the PROTAC TL13-112 caused upregulation of CD45RO both at mRNA and protein levels with minimal changes on CD45RA, overall indicating that oncogenic ALK downregulates the expression of CD45. CD45 repression was mediated by STAT3 as demonstrated by ChIP-seq data on ALCL cells treated with the ALK-TKI crizotinib or cells treated with a STAT3 degrader. Next, we found that knocking-out CD45 with the CRISPR/Cas9 system resulted in increased resistance to ALK TKI treatment and CD45 was down-regulated in ALCL cells that developed resistance
to ALK TKIs. Overall, these data suggest that CD45 expression is regulated by ALK
STAT3 and acts as a rheostat of ALK oncogenic signaling and resistance to TKI treatment in ALCL.
Abstract Additional copies of chromosome 1 long arm (1q) are frequently found in multiple myeloma (MM) and predict high-risk disease. Available data suggest a different outcome and biology of ...patients with amplification (Amp1q, ≥4 copies of 1q) vs. gain (Gain1q, 3 copies of 1q) of 1q. We evaluated the impact of Amp1q/Gain1q on the outcome of newly diagnosed MM patients enrolled in the FORTE trial (NCT02203643). Among 400 patients with available 1q data, 52 (13%) had Amp1q and 129 (32%) Gain1q. After a median follow-up of 62 months, median progression-free survival (PFS) was 21.2 months in the Amp1q group, 54.9 months in Gain1q, and not reached (NR) in Normal 1q. PFS was significantly hampered by the presence of Amp1q (HR 3.34 vs. Normal 1q, P < 0.0001; HR 1.99 vs. Gain1q, P = 0.0008). Patients with Gain1q had also a significantly shorter PFS compared with Normal 1q (HR 1.68, P = 0.0031). Concomitant poor prognostic factors or the failure to achieve MRD negativity predicted a median PFS < 12 months in Amp1q patients. Carfilzomib–lenalidomide–dexamethasone plus autologous stem cell transplantation treatment improved the adverse effect of Gain1q but not Amp1q. Transcriptomic data showed that additional 1q copies were associated with deregulation in apoptosis signaling, p38 MAPK signaling, and Myc-related genes.
Coding and long non-coding RNA (lncRNA) metabolism is now revealing its crucial role in Amyotrophic Lateral Sclerosis (ALS) pathogenesis. In this work, we present a dataset obtained via Illumina ...RNA-seq analysis on Peripheral Blood Mononuclear Cells (PBMCs) from sporadic and mutated ALS patients (mutations in FUS, TARDBP, SOD1 and VCP genes) and healthy controls. This dataset allows the whole-transcriptome characterization of PBMCs content, both in terms of coding and non-coding RNAs, in order to compare the disease state to the healthy controls, both for sporadic patients and for mutated patients. Our dataset is a starting point for the omni-comprehensive analysis of coding and lncRNAs, from an easy to withdraw, manage and store tissue that shows to be a suitable model for RNA profiling in ALS.
Caveolin-1 (Cav-1) is highly expressed in normal osteoblasts. This article reports that Cav-1 down-regulation is part of osteoblast transformation and osteosarcoma progression and validates its role ...as oncosuppressor in human osteosarcoma. A survey of 6-year follow-up indicates a better overall survival for osteosarcoma expressing a level of Cav-1 similar to osteoblasts. However, the majority of primary osteosarcoma shows significantly lower levels of Cav-1 than normal osteoblasts. Accordingly, Met-induced osteoblast transformation is associated with Cav-1 down-regulation. In vitro, osteosarcoma cell lines forced to overexpress Cav-1 show reduced malignancy with inhibited anchorage-independent growth, migration, and invasion. In vivo, Cav-1 overexpression abrogates the metastatic ability of osteosarcoma cells. c-Src and c-Met tyrosine kinases, which are activated in osteosarcoma, colocalize with Cav-1 and are inhibited on Cav-1 overexpression. Thus, Cav-1 behaves as an oncosuppressor in osteosarcoma. Altogether, data suggest that Cav-1 down-modulation might function as a permissive mechanism, which, by unleashing c-Src and Met signaling, enables osteosarcoma cells to invade neighboring tissues. These data strengthen the rationale to target c-Src family kinases and/or Met receptor to improve the extremely poor prognosis of metastatic osteosarcoma.
Platinum-based chemotherapy is the recommended first-line treatment for high-grade serous (HGS) epithelial ovarian cancer (EOC). However, most patients relapse because of platinum ...refractory/resistant disease. We aimed at assessing whether other drugs, commonly used to treat relapsed HGS-EOC and poorly active in this clinical setting, might be more effective against chemotherapy-naïve cancers. We collected couples of HGS-EOC samples from the same patients before and after neo-adjuvant platinum-based chemotherapy. Samples were propagated as Patient Derived Xenografts (PDXs) in immunocompromised mice ("xenopatients"). Xenopatients were treated in parallel with carboplatin, gemcitabine, pegylated liposomal doxorubicin (PLD) and trabectedin. PDXs derived from a naïve HSG-EOC showed responsiveness to carboplatin, trabectedin and gemcitabine. The PDXs propagated from a tumor mass of the same patient, grown after carboplatin therapy, did no longer respond to trabectedin and gemcitabine and showed heterogeneous response to carboplatin. In line, the patient experienced clinically platinum-sensitivity first and then discordant responses of different tumor sites to platinum re-challenge. Loss of PDX responsiveness to drugs was associated with 4-fold increase of NR2F2 gene expression. PDXs from another naïve tumor showed complete response to PLD, which was lost in the PDXs derived from a mass grown in the same patient after platinum-based chemotherapy. This patient showed platinum refractoriness and responded poorly to PLD as second-line treatment. PDX response to PLD was associated with high expression of TOP2A protein. PDXs demonstrated that chemotherapy-naïve HGS-EOC might display susceptibility to agents not used commonly as first line treatment. Data suggest the importance of personalizing also chemotherapy.
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