Role of Sorafenib in Overcoming Resistance of Chemotherapy-Failure Castration-Resistant Prostate Cancer

Meyer, Andrew; Cygan, Peter H.; Tolzien, Kathy; Galvez, Angel G.; Bitran, Jacob D.; Lestingi, Timothy M.; Nabhan, Chadi

doi:10.1016/j.clgc.2013.09.003

Cited by 13 publications

(11 citation statements)

References 33 publications

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“…Sorafenib is an FDA-approved small-molecule inhibitor targeting RAF family members and other kinases such as VEGFR-2, VEGFR-3, and PDGF-β (62). Clinical studies involving a small number of patients have suggested that sorafenib may have therapeutic benefit in patients with castration-resistant prostate cancer (63,64). Due to reports of paradoxical RAF inhibitor-mediated RAF activation, inhibiting the direct downstream targets of RAF, MEK1/MEK2, may be a better approach (65).…”

Section: Discussionmentioning

confidence: 99%

Functional screen identifies kinases driving prostate cancer visceral and bone metastasis

Faltermeier

Drake

Clark

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Mutationally activated kinases play an important role in the progression and metastasis of many cancers. Despite numerous oncogenic alterations implicated in metastatic prostate cancer, mutations of kinases are rare. Several lines of evidence suggest that nonmutated kinases and their pathways are involved in prostate cancer progression, but few kinases have been mechanistically linked to metastasis. Using a mass spectrometry-based phosphoproteomics dataset in concert with gene expression analysis, we selected over 100 kinases potentially implicated in human metastatic prostate cancer for functional evaluation. A primary in vivo screen based on overexpression of candidate kinases in murine prostate cells identified 20 wild-type kinases that promote metastasis. We queried these 20 kinases in a secondary in vivo screen using human prostate cells. Strikingly, all three RAF family members, MERTK, and NTRK2 drove the formation of bone and visceral metastasis confirmed by positron-emission tomography combined with computed tomography imaging and histology. Immunohistochemistry of tissue microarrays indicated that these kinases are highly expressed in human metastatic castration-resistant prostate cancer tissues. Our functional studies reveal the strong capability of select wild-type protein kinases to drive critical steps of the metastatic cascade, and implicate these kinases in possible therapeutic intervention.kinases | metastasis | prostate cancer | bone metastasis M etastatic prostate cancer is responsible for the deaths of ∼30,000 men in the United States each year (1, 2). Ninety percent of patients develop bone metastases, and other major sites of metastases include lymph nodes, liver, adrenal glands, and lung (3). First-line treatments for metastatic disease are androgen deprivation therapies that block androgen synthesis or signaling through the androgen receptor (AR) (2). Inevitably, metastatic prostate cancer becomes resistant to androgen blockade. Second-line treatments such as chemotherapy (docetaxel, cabazitaxel) and radiation only extend survival 2-4 mo (4, 5).Identifying new therapeutic targets for metastatic prostate cancer has proven difficult. Exome and whole-genome sequencing of human metastatic prostate cancer tissues have found frequent mutations and/or chromosomal aberrations in numerous genes, including AR, TP53, PTEN, BRCA2, and MYC (6-11). The precise functional contribution of these genes to prostate cancer metastasis remains unknown. Genomic and phosphoproteomic analyses have also revealed that metastatic prostate cancer is molecularly heterogeneous, which has complicated the search for common therapeutic targets (12). Few murine models of prostate cancer develop metastases. Mice having prostate-specific homozygous deletions in SMAD4 and PTEN or expression of mutant KRAS develop metastases in visceral organs but rarely in bone (13-15).Targeting genetically altered constitutively active protein kinases such as BCR-ABL in chronic myelogenous leukemia and BRAF V600E in melanoma has led to dramat...

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Section: Discussionmentioning

confidence: 99%

Functional screen identifies kinases driving prostate cancer visceral and bone metastasis

Faltermeier

Drake

Clark

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…However, research has demonstrated that, besides targeting Raf and vascular endothelial growth factor receptor (VEGFR), sorafenib also inhibits the AR and Akt in prostate cancer (17). Clinical evidence suggests that sorafenib, alone or in combination with bicalutamide (an AR inhibitor), can overcome the resistance of CRPC to chemotherapy (18,19). Ongoing studies are exploring the response of various phenotypes of prostate cancer to sorafenib.…”

Section: Introductionmentioning

confidence: 99%

Combined Anti-Cancer Effects of Platycodin D and Sorafenib on Androgen-Independent and PTEN-Deficient Prostate Cancer

Song

Zhang

et al. 2021

Front. Oncol.

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Castration-resistant (androgen-independent) and PTEN-deficient prostate cancer is a challenge in clinical practice. Sorafenib has been recommended for the treatment of this type of cancer, but is associated with several adverse effects. Platycodin D (PD) is a triterpene saponin with demonstrated anti-cancer effects and a good safety profile. Previous studies have indicated that PC3 cells (PTEN -/-, AR -/-) are sensitive to PD, suggesting that it may also be a useful treatment for castration-resistance prostate cancer. We herein investigated the effects of combining PD with sorafenib to treat PTEN-deficient prostate cancer cells. Our data show that PD promotes sorafenib-induced apoptosis and cell cycle arrest in PC3 cells. Of interest, PD only promoted the anti-cancer effects of sorafenib in Akt-positive and PTEN-negative prostate cancer cells. Mechanistic studies revealed that PD promoted p-Akt ubiquitination by increasing the p-Akt level. PD also increased the protein and mRNA expression of FOXO3a, the downstream target of Akt. Meanwhile, PD promoted the activity of FOXO3a and increased the protein expression of Fasl, Bim and TRAIL. Interestingly, when FOXO3a expression was inhibited, the antitumor effects of both PD and sorafenib were individually inhibited, and the more potent effects of the combination treatment were inhibited. Thus, the combination of PD and sorafenib may exert potent anti-cancer effects specifically via FOXO3a. The use of Akt inhibitors or FOXO3a agonists, such as PD, may represent a promising approach for the treatment of androgen-independent and PTEN-deficient prostate cancer.

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“…When PTEN is deleted, AKT regulates PC cells proliferation, while AR regulates their survival, thus offering a possible explanation of these results and supporting the rationale of combining AKT blockers with AR modulators (Sittadjody et al, 2016). This notion has guided a phase I (Meyer et al, 2014) dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 in heavily pretreated patients with mCRPC (Kolinsky et al, 2017). AZD5363 at the dosage of 300 mg twice daily four days onthree days off combined with enzalutamide 160 mg once daily was well tolerated (only one patient experienced G3 maculopapular rash) and this dosage was recommended for the following phase II trials.…”

Section: Pi3k-akt-mtor Pathwaymentioning

confidence: 77%

“…Several studies investigated the activity of sorafenib, a Raf inhibitor, both in chemotherapy-naïve (Chi et al, 2008;Safarinejad, 2010;Steinbild et al, 2007) and in pretreated unselected populations of patients with mCRPC (Aragon-Ching et al, 2009;Dahut et al, 2008;Nabhan et al, 2012), with discouraging results. Recently, Meyer et al enrolled 21 patients whose disease had progressed during chemotherapy and added sorafenib to their last chemotherapy regimen (Meyer et al, 2014). They observed biochemical response in 10/21 patients and radiographic stability in 16/21, suggesting that sorafenib may overcome chemotherapy-failure among patients with CRPC.…”

Section: Mapk-erk Pathwaymentioning

confidence: 99%

Targeting androgen-independent pathways: new chances for patients with prostate cancer?

Cattrini

Zanardi

Vallome

et al. 2017

Critical Reviews in Oncology/Hematology

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Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate cancer (PC). Most patients eventually progress to a condition known as castration-resistant prostate cancer (CRPC), characterized by lack of response to ADT. Although new androgen receptor signaling (ARS) inhibitors and chemotherapeutic agents have been introduced to overcome resistance to ADT, many patients progress because of primary or acquired resistance to these agents. This comprehensive review aims at exploring the mechanisms of resistance and progression of PC, with specific focus on alterations which lead to the activation of androgen receptor (AR)-independent pathways of survival. Our work integrates available clinical and preclinical data on agents which target these pathways, assessing their potential clinical implication in specific settings of patients. Given the rising interest of the scientific community in cancer immunotherapy strategies, further attention is dedicated to the role of immune evasion in PC.

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Role of Sorafenib in Overcoming Resistance of Chemotherapy-Failure Castration-Resistant Prostate Cancer

Cited by 13 publications

References 33 publications

Functional screen identifies kinases driving prostate cancer visceral and bone metastasis

Functional screen identifies kinases driving prostate cancer visceral and bone metastasis

Combined Anti-Cancer Effects of Platycodin D and Sorafenib on Androgen-Independent and PTEN-Deficient Prostate Cancer

Targeting androgen-independent pathways: new chances for patients with prostate cancer?

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