In pursuit of synergy: An investigation of the PI3K/mTOR/MEK co-targeted inhibition strategy in NSCLC

Heavey, Susan; Cuffe, Sinéad; Finn, Stephen P.; Young, Vincent; Ryan, Ronan; Nicholson, Siobhan; Leonard, Niamh; McVeigh, Niall; Barr, Martin P.; O’Byrne, Kenneth J.; Gately, Kathy

doi:10.18632/oncotarget.12755

Cited by 25 publications

(15 citation statements)

References 34 publications

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“…In fact, this cell line began to exhibit decreased sensitivity to the drug after just one month, and developed a log fold difference in IC50 concentration between parent (H1975GP) and resistant (H1975GR) cell lines after just 4 months of treatment with Apitolisib (GDC-0980). H1975 cells were shown to harbour mutations in both PIK3CA and PIK3R1 , and have previously been shown to express PI3K pathway signalling phosphoproteins more highly than the other cell lines used here 32 .…”

Section: Discussionmentioning

confidence: 82%

Development and characterisation of a panel of phosphatidylinositide 3-kinase – mammalian target of rapamycin inhibitor resistant lung cancer cell lines

Heavey

Dowling

Moore

et al. 2018

Sci Rep

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The PI3K-mTOR pathway is involved in regulating all hallmarks of cancer, and is often dysregulated in NSCLC, making it an attractive therapeutic target in this setting. Acquired resistance to PI3K-mTOR inhibition is a major hurdle to overcome in the success of PI3K-mTOR targeted agents. H460, A549, and H1975 resistant cells were generated by prolonged treatment in culture with Apitolisib (GDC-0980), a dual PI3K-mTOR inhibitor over a period of several months, from age-matched parent cells. Resistance was deemed to have developed when a log fold difference in IC50 had been achieved. Resistant cell lines also exhibited resistance to another widely investigated PI3K-mTOR dual inhibitor; Dactolisib (BEZ235). Cell lines were characterised at the level of mRNA (expression array profiling expression of >150 genes), miRNA (expression array profiling of 2100 miRNAs), protein (bottoms-up label-free mass spectrometry) and phosphoprotein (expression array profiling of 84 phospho/total proteins). Key alterations were validated by qPCR and Western blot. H1975 cells were initially most sensitive to Apitolisib (GDC-0980), but developed resistance more quickly than the other cell lines, perhaps due to increased selective pressure from the impressive initial effect. In-depth molecular profiling suggested epithelial-mesenchymal transition (EMT) may play a role in resistance to PI3K-mTOR dual inhibition in NSCLC.

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Section: Discussionmentioning

confidence: 82%

Development and characterisation of a panel of phosphatidylinositide 3-kinase – mammalian target of rapamycin inhibitor resistant lung cancer cell lines

Heavey

Dowling

Moore

et al. 2018

Sci Rep

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“…However, recently a growing body of evidence has shown that it could do more in NSCLC and TKI resistance especially take PTEN/PI3K/AKT pathway into consideration [ 16 ]. Since clinical PI3K inhibition has been somewhat disappointing, people are now trying to co-inhibit PI3K with other factors at the same time to achieve a better outcome [ 17 , 18 ]. MMP9 is closely associated with cancer, due to its role in extracellular matrix remodeling and angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Plasma microRNA alterations between EGFR-activating mutational NSCLC patients with and without primary resistance to TKI

Pan

et al. 2017

Oncotarget

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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have obtained excellent therapeutic effects against non-small cell lung cancer (NSCLC) harboring activating EGFR mutations. However, some patients have exhibited primary resistance which becomes a major obstacle in effective treatment of NSCLC. The mechanisms of EGFR-TKIs resistance involved are still poorly understood. Many studies suggest that miRNAs play an important role in regulating drug sensitivity of EGFR-TKIs. The aim of the present study was to examine differentially expressed miRNAs in plasma between EGFR-TKIs sensitive and EGFR-TKIs primary resistance patients. MiRNA microarray of plasma from patients’ blood identified 16 differentially expressed miRNAs of which 15 (hsv2-miR-H19, hsa-miR-744-5p, hsa-miR-3196, hsa-miR-3153, hsa-miR-4791, hsa-miR-4803, hsa-miR-4796-3p, hsa-miR-372-5p, hsa-miR-138-2-3p, hsa-miR-16-1-3p, hsa-miR-1469, hsa-miR-585-3p, ebv-miR-BART14-5p, hsa-miR-769-3p, hsa-miR-548aq-5p) were down regulated while only hsa-miR-503-3p was up regulated in primary resistant patients’ plasma. Volcano plot and hierarchical clustering were performed to examine the accuracy of the miRNAs. Then validation with quantitative real-time PCR was performed and the result was in accordance with the array data. Functional analysis of these differentially expressed miRNAs with Ingenuity Pathway Analysis (IPA) revealed a common signaling network including MYC, CCND1, IGF1 and RELA. In conclusion, our finding may play important role in understanding the mechanisms underlying the problem and should be further evaluated as potential biomarkers in primary resistance of NSCLC.

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“…66 However, many have exhibited issues with toxicity or resistance due to compensatory mechanisms and feedback loops with closely related signaling pathways, and co-targeted inhibition approaches have been gaining popularity in preclinical studies. [67][68][69][70] Thus, PIM and PI3K co-targeting may be a viable approach owing to the overlap between those pathways, the proven PIMinduced resistance to PI3K inhibition 35 and the reported successful synergism that results when both are used. 71 Synergy between inhibitors could allow the use of lower therapeutic doses to achieve the same clinical effect, thus potentially reducing treatment toxicity and improving patient quality of life.…”

Section: Pim Inhibition Within the Prostate Cancer Clinical Pathwaymentioning

confidence: 99%

PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer

Luszczak

Kumar

Sathyadevan

et al. 2020

Sig Transduct Target Ther

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PIM kinases have been shown to play a role in prostate cancer development and progression, as well as in some of the hallmarks of cancer, especially proliferation and apoptosis. Their upregulation in prostate cancer has been correlated with decreased patient overall survival and therapy resistance. Initial efforts to inhibit PIM with monotherapies have been hampered by compensatory upregulation of other pathways and drug toxicity, and as such, it has been suggested that co-targeting PIM with other treatment approaches may permit lower doses and be a more viable option in the clinic. Here, we present the rationale and basis for cotargeting PIM with inhibitors of PI3K/mTOR/AKT, JAK/STAT, MYC, stemness, and RNA Polymerase I transcription, along with other therapies, including androgen deprivation, radiotherapy, chemotherapy, and immunotherapy. Such combined approaches could potentially be used as neoadjuvant therapies, limiting the development of resistance to treatments or sensitizing cells to other therapeutics. To determine which drugs should be combined with PIM inhibitors for each patient, it will be key to develop companion diagnostics that predict response to each co-targeted option, hopefully providing a personalized medicine pathway for subsets of prostate cancer patients in the future.

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In pursuit of synergy: An investigation of the PI3K/mTOR/MEK co-targeted inhibition strategy in NSCLC

Cited by 25 publications

References 34 publications

Development and characterisation of a panel of phosphatidylinositide 3-kinase – mammalian target of rapamycin inhibitor resistant lung cancer cell lines

Development and characterisation of a panel of phosphatidylinositide 3-kinase – mammalian target of rapamycin inhibitor resistant lung cancer cell lines

Plasma microRNA alterations between EGFR-activating mutational NSCLC patients with and without primary resistance to TKI

PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer

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