Phase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors

Juric, Dejan; Krop, Ian E.; Ramanathan, Ramesh K.; Wilson, Timothy R.; Ware, Joseph A.; Bohórquez, Sandra M. Sanabria; Savage, Heidi; Sampath, Deepak; Salphati, Laurent; Lin, Ray; Jin, Huan; Parmar, Hema; Hsu, Jerry Y.; Hoff, Daniel D. Von; Baselga, José

doi:10.1158/2159-8290.cd-16-1080

Cited by 136 publications

(132 citation statements)

References 36 publications

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“…We used trametinib, which is a potent and selective MEK1/2 inhibitor that was approved by the Food and Drug Administration for the treatment of BRAF V600E‐mutant NSCLC in combination with the BRAF inhibitor dabrafenib . For PI3K inhibition, we selected taselisib, which has been shown in early‐phase clinical trials to be of clinical benefit for solid tumors harboring PIK3CA alterations . The details about these cell lines, the reagents, and the antibodies for western blot analysis are included in the Data .…”

Section: Methodsmentioning

confidence: 99%

Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR‐TKIs in non‐small cell lung cancer

et al. 2018

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Compensatory activation of the signal transduction pathways is one of the major obstacles for the targeted therapy of non‐small cell lung cancer (NSCLC). Herein, we present the therapeutic strategy of combined targeted therapy against the MEK and phosphoinositide‐3 kinase (PI3K) pathways for acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC. We investigated the efficacy of combined trametinib plus taselisib therapy using experimentally established EGFR‐TKI‐resistant NSCLC cell lines. The results showed that the feedback loop between MEK/ERK and PI3K/AKT pathways had developed in several resistant cell lines, which caused the resistance to single‐agent treatment with either inhibitor alone. Meanwhile, the combined therapy successfully regulated the compensatory activation of the key intracellular signals and synergistically inhibited the cell growth of those cells in vitro and in vivo. The resistance mechanisms for which the dual kinase inhibitor therapy proved effective included (MET) mesenchymal‐epithelial transition factor amplification, induction of epithelial‐to‐mesenchymal transition (EMT) and EGFR T790M mutation. In further analysis, the combination therapy induced the phosphorylation of p38 MAPK signaling, leading to the activation of apoptosis cascade. Additionally, long‐term treatment with the combination therapy induced the conversion from EMT to mesenchymal‐to‐epithelial transition in the resistant cell line harboring EMT features, restoring the sensitivity to EGFR‐TKI. In conclusion, our results indicate that the combined therapy using MEK and PI3K inhibitors is a potent therapeutic strategy for NSCLC with the acquired resistance to EGFR‐TKIs.

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Section: Methodsmentioning

confidence: 99%

Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR‐TKIs in non‐small cell lung cancer

et al. 2018

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“…Taselisib (GDC-0032; Table S1) inhibits p110α, p110γ and p110δ but not p110β, and furthermore has some selectivity for PIK3CA mutant proteins. A phase I dose-escalation trial of taselisib reported a 36% response rate for patients with PIK3CA mutant tumors, versus 0% in patients whose tumors lacked a PIK3CA hotspot mutation (Juric et al, 2017). In a phase 2 trial of fulvestrant plus taselisib, patients with ER+, mutant PIK3CA -expressing breast cancer had substantially better overall responses than patients with wild-type PIK3CA tumors (Dickler et al, 2016).…”

Section: Therapeutic Targeting Of the Pi3k Pathway In Cancermentioning

confidence: 99%

The PI3K Pathway in Human Disease

Fruman

Chiu

Hopkins

et al. 2017

Cell

1,886

1,658

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Phosphoinositide 3-kinase (PI3K) activity is stimulated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is considered a hallmark of cancer. Many PI3K pathway-targeted therapies have been tested in oncology trials, resulting in regulatory approval of one isoform-selective inhibitor (idelalisib) for treatment of certain blood cancers, and a variety of other agents at different stages of development. In parallel to PI3K research by cancer biologists, investigations in other fields have uncovered exciting and often unpredicted roles for PI3K catalytic and regulatory subunits in normal cell function and in disease. Many of these functions impinge upon oncology by influencing the efficacy and toxicity of PI3K-targeted therapies. Here we provide a perspective on the roles of class I PI3Ks in the regulation of cellular metabolism and in immune system functions, two topics closely intertwined with cancer biology. We also discuss recent progress developing PI3K-targeted therapies for treatment of cancer and other diseases.

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“…PI3Kα inhibitors have shown improved clinical outcome in estrogen receptor (ER)-positive and PIK3CA mutant breast cancers that have elevated PI3K signaling (Juric et al, 2017, 2018), but not all tumors are sensitive to these inhibitors. We have observed a highly uniform adaptive tumor response to PI3K inhibitors that is characterized by an increase in ER-dependent transcription, which mediates therapeutic resistance (Bosch et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

PI3K Inhibition Activates SGK1 via a Feedback Loop to Promote Chromatin-Based Regulation of ER-Dependent Gene Expression

et al. 2019

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SUMMARY The PI3K pathway integrates extracellular stimuli to phosphorylate effectors such as AKT and serum-and-glucocorticoid-regulated kinase (SGK1). We have previously reported that the PI3K pathway regulates estrogen receptor (ER)-dependent transcription in breast cancer through the phosphorylation of the lysine methyltransferase KMT2D by AKT. Here, we show that PI3Kα inhibition, via a negative-feedback loop, activates SGK1 to promote chromatin-based regulation of ER-dependent transcription. PI3K/AKT inhibitors activate ER, which promotes SGK1 transcription through direct binding to its promoter. Elevated SGK1, in turn, phosphorylates KMT2D, suppressing its function, leading to a loss of methylation of lysine 4 on histone H3 (H3K4) and a repressive chromatin state at ER loci to attenuate ER activity. Thus, SGK1 regulates the chromatin landscape and ER-dependent transcription via the direct phosphorylation of KMT2D. These findings reveal an ER-SGK1-KMT2D signaling circuit aimed to attenuate ER response through a role for SGK1 to program chromatin and ER transcriptional output.

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Phase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors

Cited by 136 publications

References 36 publications

Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR‐TKIs in non‐small cell lung cancer

Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR‐TKIs in non‐small cell lung cancer

The PI3K Pathway in Human Disease

PI3K Inhibition Activates SGK1 via a Feedback Loop to Promote Chromatin-Based Regulation of ER-Dependent Gene Expression

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