Synergistic anticancer efficacy of MEK inhibition and dual PI3K/mTOR inhibition in castration‐resistant prostate cancer

Park, Hongzoo; Kim, Yunlim; Sul, Jee-Won; Jeong, In Gab; Yi, Hye-Jin; Ahn, Jae Beom; Kang, Jong Soon; Yun, Jieun; Hwang, Jung Jin; Kim, Choung‐Soo

doi:10.1002/pros.23057

Cited by 25 publications

(21 citation statements)

References 29 publications

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“…While we did not observe any significant decrease in Ki67 with the combination, this may be related to collecting all of our tumors at the end of study at which point the xenograft tumors were treatment-resistant. Recently, Park et al, showed the combination of selumitinib and the pan-PI3K inhibitor GSK2126458 improved tumor growth inhibition compared to either monotherapy in AR-negative DU145 and PC3 xenografts [42]. Overall, their results in AR-negative models are comparable to our results.…”

Section: Discussionsupporting

confidence: 82%

Combined Akt and MEK pathway blockade in pre-clinical models of enzalutamide-resistant prostate cancer.

Toren¹,

Kim²,

Fazli³

et al. 2016

JCO

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Despite recent improvements in patient outcomes using newer androgen receptor (AR) pathway inhibitors, treatment resistance in castrate resistant prostate cancer (CRPC) continues to remain a clinical problem. Co-targeting alternate resistance pathways are of significant interest to treat CRPC and delay the onset of resistance. Both the AKT and MEK signaling pathways become activated as prostate cancer develops resistance to AR-targeted therapies. This pre-clinical study explores co-targeting these pathways in AR-positive prostate cancer models. Using various in vitro models of prostate cancer disease states including androgen dependent (LNCaP), CRPC (V16D and 22RV1) and ENZ-resistant prostate cancer (MR49C and MR49F), we evaluate the relevance of targeting both AKT and MEK pathways. Our data reveal that AKT inhibition induces apoptosis and inhibits cell growth in PTEN null cell lines independently of their sensitivity to hormone therapy; however, AKT inhibition had no effect on the PTEN positive 22RV1 cell line. Interestingly, we found that MEK inhibition had greater effect on 22RV1 cells compared to LNCaP, V16D or ENZ-resistant cells MR49C and MR49F cells. In vitro, combination AKT and MEK blockade had evidence of synergy observed in some cell lines and assays, but this was not consistent across all results. In vivo, the combination of AKT and MEK inhibition resulted in more consistent tumor growth inhibition of MR49F xenografts and longer disease specific survival compared to AKT inhibitor monotherapy. As in our in vitro study, 22RV1 xenografts were more resistant to AKT inhibition while they were more sensitive to MEK inhibition. Our results suggest that targeting AKT and MEK in combination may be a valuable strategy in prostate cancer when both pathways are activated and further support the importance of characterizing the dominant oncogenic pathway in each patient's tumor in order to select optimal therapy.

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Section: Discussionsupporting

confidence: 82%

Combined Akt and MEK pathway blockade in pre-clinical models of enzalutamide-resistant prostate cancer.

Toren¹,

Kim²,

Fazli³

et al. 2016

JCO

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“…The gene panel we utilized covers several key genomic aberrations that are of emerging interest as possible clinical predictive biomarkers that may be actionable in prostate cancer, including loss of PTEN, gain of PIK3CA (both may sensitize tumors to PI3K/AKT pathway inhibition; refs. 18,19), and amplification of MYC (MYC-driven tumors have been reported to sensitize to AURA and BET inhibition and can result in replication stress; ref. 20).…”

Section: Discussionmentioning

confidence: 99%

Gene Copy Number Estimation from Targeted Next-Generation Sequencing of Prostate Cancer Biopsies: Analytic Validation and Clinical Qualification

Seed

Yuan

Mateo

et al. 2017

Clinical Cancer Research

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Purpose: Precise detection of copy number aberrations (CNA) from tumor biopsies is critically important to the treatment of metastatic prostate cancer. The use of targeted panel next-generation sequencing (NGS) is inexpensive, high throughput, and easily feasible, allowing single-nucleotide variant calls, but CNA estimation from this remains challenging.Experimental Design: We evaluated CNVkit for CNA identification from amplicon-based targeted NGS in a cohort of 110 fresh castration-resistant prostate cancer biopsies and used capture-based whole-exome sequencing (WES), array comparative genomic hybridization (aCGH), and FISH to explore the viability of this approach.Results: We showed that this method produced highly reproducible CNA results (r ¼ 0.92), with the use of pooled germline DNA as a coverage reference supporting precise CNA estimation.CNA estimates from targeted NGS were comparable with WES (r ¼ 0.86) and aCGH (r ¼ 0.7); for key selected genes (BRCA2, MYC, PIK3CA, PTEN, and RB1), CNA estimation correlated well with WES (r ¼ 0.91) and aCGH (r ¼ 0.84) results. The frequency of CNAs in our population was comparable with that previously described (i.e., deep deletions: BRCA2 4.5%; RB1 8.2%; PTEN 15.5%; amplification: AR 45.5%; gain: MYC 31.8%). We also showed, utilizing FISH, that CNA estimation can be impacted by intratumor heterogeneity and demonstrated that tumor microdissection allows NGS to provide more precise CNA estimates.Conclusions: Targeted NGS and CNVkit-based analyses provide a robust, precise, high-throughput, and cost-effective method for CNA estimation for the delivery of more precise patient care.

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“…GSK2126458 (GlaxoSmithKline, Brentford, UK) has demonstrated a broad spectrum of in vitro and in vivo activity, including the sensitization of nasopharyngeal carcinoma to radiation [69]. Synergistic antitumor activity has also been demonstrated with dual PI3K/mTOR inhibition in combination with MEK inhibition in castrate-resistant prostate cancer cells [70]. An FIH doseescalation study of GSK2126458 in 170 patients with refractory cancers (NCT00972686) reported diarrhea and rash as the most frequent grade 3 or higher AEs (8% and 5%, respectively), and durable responses were observed in patients with sarcoma, renal cell carcinoma, breast, endometrial, oropharyngeal, and bladder cancers irrespective of PIK3CA mutation status [71].…”

Section: Gsk2126458mentioning

confidence: 99%

Phosphoinositide 3-kinase (PI3K) pathway inhibitors in solid tumors: From laboratory to patients

Janků

2017

Cancer Treatment Reviews

199

137

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The phosphoinositide 3-kinase (PI3K) pathway is an intracellular signaling pathway that has regulatory roles in cell survival, proliferation, and differentiation, and a critical role in tumorigenesis. In cancer, multiple studies have investigated the therapeutic targeting of the PI3K pathway, and multiple inhibitors targeting PI3K and its isoforms, protein kinase B/AKT, mammalian target of rapamycin (mTOR), and other pathway proteins have been developed. For the treatment of solid tumors, only allosteric mTOR inhibitors, such as everolimus and temsirolimus, are currently approved for clinical use. This review describes the PI3K inhibitors that have progressed from the laboratory to late-stage clinical trials, and discusses the challenges that have prevented other compounds from doing the same. Challenges to the therapeutic effectiveness of some PI3K inhibitors include the absence of reliable and effective biomarkers, their limited efficacy as single agents, insufficient development of rational therapeutic combinations, the use of schedules with a variety of off-target effects, and suboptimal therapeutic exposures. Therefore, with regard to PI3K inhibitors currently in late-stage clinical trials, the identification of appropriate biomarkers of efficacy and the development of optimal combination regimens and dosing schedules are likely to be important for graduation into clinical practice.

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Synergistic anticancer efficacy of MEK inhibition and dual PI3K/mTOR inhibition in castration‐resistant prostate cancer

Abstract: The combination of GSK2126458 and AZD6244 blocks both the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways simultaneously and is an effective strategy for the treatment of CRPCs.

Cited by 25 publications

References 29 publications

Combined Akt and MEK pathway blockade in pre-clinical models of enzalutamide-resistant prostate cancer.

Combined Akt and MEK pathway blockade in pre-clinical models of enzalutamide-resistant prostate cancer.

Gene Copy Number Estimation from Targeted Next-Generation Sequencing of Prostate Cancer Biopsies: Analytic Validation and Clinical Qualification

Phosphoinositide 3-kinase (PI3K) pathway inhibitors in solid tumors: From laboratory to patients

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