ERK-TSC2 signalling in constitutively-active HRAS mutant HNSCC cells promotes resistance to PI3K inhibition

Ruicci, Kara M.; Pinto, Nicole; Khan, Mohammed I.; Yoo, John; Fung, Kevin; MacNeil, Danielle; Mymryk, Joe S.; Barrett, John W.; Nichols, Anthony C.

doi:10.1016/j.oraloncology.2018.07.010

Cited by 29 publications

(25 citation statements)

References 27 publications

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“…In head and neck squamous cell cancer patients who were non-response to PI3K targeted therapy, mTOR inhibitor in combination with MAPK inhibitor promoted resistance to PI3K inhibition. 58 So to this end, miR-106/ CIC/MAPK signaling axis may be a promising therapeutic strategy for chemoresistance subset of RCC tumors.…”

Section: Discussionmentioning

confidence: 99%

<p>miR-106b promotes proliferation and invasion by targeting Capicua through MAPK signaling in renal carcinoma cancer</p>

Miao¹,

Shu²,

Zhuang³

et al. 2019

OTT

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Background: miR-106b has been reported to play a vital role in pathogenesis of some types of cancer, whilst the role of miR-106b in renal carcinoma cancer (RCC) remains unknown. Purpose: The objective of this study was to identify the mechanism of miR-106b regulating the progression of renal carcinoma. Method: The expression of miR-106b was analyzed in RCC cell lines, RCC and adjacent normal renal tissues through qRT-PCR assays. Target mRNA of miR-106b was predicted with databases and verified by luciferase reporter assays. And the effects of miR-106b or targeted mRNA on cell proliferation, invasion, the process of epithelial-mesenchymal transitions (EMTs) were assessed in vitrothrough CCK-8, transwell cell invasion assays, qRT-PCR and Western blotting assays respectively. In addition, the effects of miR-106b on the growth of xenografts mice were analyzedin vivo. Results: The results demonstrated that miR-106b was significantly increased both in RCC tissues and cell lines. Luciferase reporter assays revealed that miR-106b inhibited Capicua expression by targeting its 3ʹ-UTR sequence. And miR-106b promoted cell proliferation, invasion, EMT progression in RCC cellin vitro, as well as promoted the tumor growth of 786-O cells derived xenografts mice. Additionally, loss of Capicua promoted the activation of MAPK signaling pathway. Conclusion: The study suggested that miR-106b regulated RCC progression through MAPK signaling pathway partly by targeting Capicua, which might provide valuable evidence for therapeutic target development of RCC.

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Section: Discussionmentioning

confidence: 99%

<p>miR-106b promotes proliferation and invasion by targeting Capicua through MAPK signaling in renal carcinoma cancer</p>

Miao¹,

Shu²,

Zhuang³

et al. 2019

OTT

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“…The RAS-RAF-MEK-ERK signaling pathway is highly interconnected with PI3K signaling [174]. Mutation and overexpression of HRAS which belongs to the RAS family has been shown to reduced susceptibility to PI3K inhibitor, while knockdown improved sensitivity [175]. Further, interactions between NEK9 and MAP2K4 have been proposed to mediate cancer cell proliferation and resistance to PI3K inhibitors [176].…”

Section: Resistancesmentioning

confidence: 99%

Targeting PI3K in cancer: mechanisms and advances in clinical trials

et al. 2019

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Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling is one of the most important intracellular pathways, which can be considered as a master regulator for cancer. Enormous efforts have been dedicated to the development of drugs targeting PI3K signaling, many of which are currently employed in clinical trials evaluation, and it is becoming increasingly clear that PI3K inhibitors are effective in inhibiting tumor progression. PI3K inhibitors are subdivided into dual PI3K/mTOR inhibitors, pan-PI3K inhibitors and isoform-specific inhibitors. In this review, we performed a critical review to summarize the role of the PI3K pathway in tumor development, recent PI3K inhibitors development based on clinical trials, and the mechanisms of resistance to PI3K inhibition.

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“…The rationale for combining pathways inhibitors to prevent PI3Ki resistance has been shown to achieve extended response in pre-clinical HNSCC models. For example, by simultaneously blocking mTORC2 [ 30 , 31 ], human epidermal growth factor receptor 3 (HER3) [ 32 , 33 ], Epidermal growth factor receptor (EGFR) [ 34 , 35 ], Jun N-terminal kinases (JNK) [ 36 ], Extracellular signal-regulated kinases (ERK) [ 37 ], and AXL [ 22 ]. Previously, Vora et al [ 23 ] and others [ 26 ] described in both pre-clinical breast cancer models and in patients, that resistance to BYL719 is mediated by sustained activation of mTORC1 that regulates the CDK 4/6–Rb axis.…”

Section: Discussionmentioning

confidence: 99%

CDK 4/6 Inhibition Overcomes Acquired and Inherent Resistance to PI3Kα Inhibition in Pre-Clinical Models of Head and Neck Squamous Cell Carcinoma

Remer

Badarni

Hikri

et al. 2020

JCM

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Activating alterations in PIK3CA, the gene coding for the catalytic subunit of phosphoinositide-3-kinase (PI3K), are prevalent in head and neck squamous cell carcinoma (HNSCC) and thought to be one of the main drivers of these tumors. However, early clinical trials on PI3K inhibitors (PI3Ki) have been disappointing due to the limited durability of the activity of these drugs. To investigate the resistance mechanisms to PI3Ki and attempt to overcome them, we conducted a molecular-based study using both HNSCC cell lines and patient-derived xenografts (PDXs). We sought to simulate and dissect the molecular pathways that come into play in PIK3CA-altered HNSCC treated with isoform-specific PI3Ki (BYL719, GDC0032). In vitro assays of cell viability and protein expression indicate that activation of the mTOR and cyclin D1 pathways is associated with resistance to PI3Ki. Specifically, in BYL719-resistant cells, BYL719 treatment did not induce pS6 and pRB inhibition as detected in BYL719-sensitive cells. By combining PI3Ki with either mammalian target of rapamycin complex 1 (mTORC1) or cyclin D1 kinase (CDK) 4/6 specific inhibitors (RAD001 and abemaciclib, respectively), we were able to overcome the acquired resistance. Furthermore, we found that PI3Ki and CDK 4/6 inhibitors have a synergistic anti-tumor effect when combined in human papillomavirus (HPV)-negative/PIK3CA-WT tumors. These findings provide a rationale for combining PI3Ki and CDK 4/6 inhibitors to enhance anti-tumor efficacy in HNSCC patients.

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ERK-TSC2 signalling in constitutively-active HRAS mutant HNSCC cells promotes resistance to PI3K inhibition

Cited by 29 publications

References 27 publications

<p>miR-106b promotes proliferation and invasion by targeting Capicua through MAPK signaling in renal carcinoma cancer</p>

<p>miR-106b promotes proliferation and invasion by targeting Capicua through MAPK signaling in renal carcinoma cancer</p>

Targeting PI3K in cancer: mechanisms and advances in clinical trials

CDK 4/6 Inhibition Overcomes Acquired and Inherent Resistance to PI3Kα Inhibition in Pre-Clinical Models of Head and Neck Squamous Cell Carcinoma

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