Molecular Basis of Drug Resistance and Insights for New Treatment Approaches in mCRPC

Giacinti, Silvana; Poti, Giulia; Roberto, Michela; Macrini, Serena; Bassanelli, Maria; Pietro, Francesca Di; Aschelter, Anna Maria; Ceribelli, Anna; Ruggeri, Enzo Maria; Marchetti, Paolo

doi:10.21873/anticanres.12953

Cited by 23 publications

(19 citation statements)

References 67 publications

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“…miR-148 also restored sensitivity to PTX by transfecting ectopic miR-148 into resistant cells [305,413,417]. Interestingly, the regulation of E-cadherin and ZEB1 has been correlated with expression of members of the miR200 family; the reduction of the miR-200 members allows for increased ZEB1 expression, which negatively regulates E-cadherin [379,421]. Transfection of miR-200 members into CRPC cells increased E-cadherin and increased DTX-induced apoptosis [379].…”

Section: Mirnasmentioning

confidence: 99%

Mechanisms of Taxane Resistance

Maloney

Hoover

Morejon-Lasso

et al. 2020

Cancers

118

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The taxane family of chemotherapy drugs has been used to treat a variety of mostly epithelial-derived tumors and remain the first-line treatment for some cancers. Despite the improved survival time and reduction of tumor size observed in some patients, many have no response to the drugs or develop resistance over time. Taxane resistance is multi-faceted and involves multiple pathways in proliferation, apoptosis, metabolism, and the transport of foreign substances. In this review, we dive deeper into hypothesized resistance mechanisms from research during the last decade, with a focus on the cancer types that use taxanes as first-line treatment but frequently develop resistance to them. Furthermore, we will discuss current clinical inhibitors and those yet to be approved that target key pathways or proteins and aim to reverse resistance in combination with taxanes or individually. Lastly, we will highlight taxane response biomarkers, specific genes with monitored expression and correlated with response to taxanes, mentioning those currently being used and those that should be adopted. The future directions of taxanes involve more personalized approaches to treatment by tailoring drug–inhibitor combinations or alternatives depending on levels of resistance biomarkers. We hope that this review will identify gaps in knowledge surrounding taxane resistance that future research or clinical trials can overcome.

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Section: Mirnasmentioning

confidence: 99%

Mechanisms of Taxane Resistance

Maloney

Hoover

Morejon-Lasso

et al. 2020

Cancers

118

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“…In particular, emergence of point mutations as a response to antiandrogen therapy is a quite common event, which may result in antiandrogens acting as agonists rather than antagonists with severe clinical consequences (Knudsen & Penning 2010, Joseph et al 2013, Schrecengost & Knudsen 2013, Lorente et al 2015, Watson et al 2015, Jernberg et al 2017, Giacinti et al 2018. The identification of constitutively active, truncated splice AR variants (AR-Vs) lacking parts or the entire LBD also poses important pharmacological challenges (Dehm & Tindall 2011, Centenera et al 2013b, Ho & Dehm 2017, Paschalis et al 2018.…”

Section: Implications For the Development Of Novel Therapeutic Stratementioning

confidence: 99%

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

Jiménez-Panizo

Pérez

Rojas

et al. 2019

Endocrine-Related Cancer

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Nuclear receptors are transcription factors that play critical roles in development, homeostasis and metabolism in all multicellular organisms. An important family of nuclear receptors comprises those members that respond to steroid hormones, and which is subdivided in turn into estrogen receptor (ER) isoforms α and β (NR3A1 and A2, respectively), and a second subfamily of so-called oxosteroid receptors. The latter includes the androgen receptor (AR/NR3C4), the glucocorticoid receptor (GR/NR3C1), the mineralocorticoid receptor (MR/NR3C2) and the progesterone receptor (PR/NR3C3). Here we review recent advances in our understanding of the structure-and-function relationship of steroid nuclear receptors and discuss their implications for the etiology of human diseases. We focus in particular on the role played by AR dysregulation in both prostate cancer (PCa) and androgen insensitivity syndromes (AIS), but also discuss conditions linked to mutations of the GR gene as well as those in a non-steroidal receptor, the thyroid hormone receptor (TR). Finally, we explore how these recent results might be exploited for the development of novel and selective therapeutic strategies.

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“…Earlier studies also revealed association of EGFR expression with androgen receptor independence nullifying the role of anti-androgen therapy in these patients. Clinical trials involving the use of specific therapies are complex in design and require restricted ethical care [15,16]. Therefore, role of these new therapeutic options like anti-EGFR therapy should be evaluated in patients with…”

Section: Discussionmentioning

confidence: 99%

Prognostic utility of epidermal growth factor receptor (EGFR) expression in prostatic acinar adenocarcinoma

Hashmi

Irfan

et al. 2019

Appl Cancer Res

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Background: Epidermal growth factor receptor (EGFR) is potential prognostic biomarker expressed in many human cancers. Prognostic significance of EGFR immunohistochemical expression has not been established in prostatic acinar adenocarcinoma, therefore we aimed to evaluate the frequency of expression of EGFR in prostatic adenocarcinoma and its association with other prognostic parameters. Methods: The study included 123 cases of biopsy proven prostatic acinar adenocarcinoma treated at Liaquat National hospital, Karachi from January 2013 till December 2017. Paraffin blocks of all cases were retrieved; sections were cut and stained with haematoxylin and eosin. Pathologic characteristics including tumor quantification, WHO grade group, gleason score, perineural and lymphovascular invasion were evaluated. EGFR immunohistochemistry (IHC) was performed on all tissue blocks. Results: Mean age of the patients included in the study was 69.05 ± 8.68 years. High gleason scores i.e. 8 & 9 were noted in 22% (27 cases) and 22.8% (28 cases) respectively. Similarly, 22.8% (28 cases) showed WHO grade group 5. 52.8% (65 cases) had > 50% tissue involvement by carcinoma and perineural invasion was seen in 37.4% (46 cases). Positive EGFR expression was noted in 18.7% (23 cases), while 81.3% (100 cases) showed negative EGFR expression. Significant association of EGFR expression was noted with gleason score (p-value = < 0.001), WHO grade (p = < 0.001), tumor quantification (p = 0.007) and perineural invasion (p = < 0.001). Moreover, significant association of EGFR expression was also seen with disease recurrence and Her2neu over expression. Patients with low gleason scores (score 6 and 7) and lower grade group (1, 2 & 3) were less likely to have positive EGFR expression as compared to patients with high gleason score (score 9) and higher grade group (5). Similarly, patients with perineural invasion were more likely to have positive EGFR expression. Conclusion: We found a relatively low EGFR expression in our patients with prostatic adenocarcinoma; however, its association with poor prognostic parameters like high gleason score, higher grade group, perineural invasion, higher tissue involvement by cancer and disease recurrence signifies its importance as a prognostic parameter in prostatic acinar adenocarcinoma.

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Molecular Basis of Drug Resistance and Insights for New Treatment Approaches in mCRPC

Cited by 23 publications

References 67 publications

Mechanisms of Taxane Resistance

Mechanisms of Taxane Resistance

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

Prognostic utility of epidermal growth factor receptor (EGFR) expression in prostatic acinar adenocarcinoma

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