scholarly journals Integrated Molecular Profiling as an Approach to Identify PI3K Inhibitor Resistance Mechanisms

2020 ◽  
Author(s):  
Nicole L. Michmerhuizen ◽  
Jiayu Wang ◽  
J. Chad Brenner
Keyword(s):  
Cancer Biology ◽  
Predictive Biomarkers ◽  
Resistance Mechanisms ◽  
Pi3k Pathway ◽  
Pi3k Inhibitor ◽  
Pi3k Inhibitors ◽  
Technological Advances ◽  
Cancer Field ◽  
Important Challenge ◽  
Inhibitor Resistance

The identification of drug resistance pathways and approaches to target these pathways remains a significant and important challenge in cancer biology. Here, we address this challenge in the context of ongoing efforts to advance phosphatidylinositol 3-kinase (PI3K) inhibitors for the treatment of PI3K-aberrant cancers. While PI3K inhibitors have had tremendous success in some diseases, such as breast cancer, early clinical trials in other malignancies, such as head and neck squamous cell carcinoma (HNSCC), have not had the same level of success. Since HNSCC and other cancers display relatively high PI3K pathway alteration rates (>45%), these underwhelming results suggest that additional or unexpected factors may contribute to the lower response rates. Here, we highlight some of the emerging functional genomic and sequencing approaches being used to identify predictive biomarkers of PI3K inhibitor response using both cancer cell lines and clinical trial specimens. Importantly, these approaches have uncovered both innate genetic and adaptive mechanisms driving PI3K inhibitor resistance. In this chapter, we describe recent technological advances that have revolutionized our understanding of PI3K inhibitor resistance pathways in HNSCC and highlight how these and other approaches lay the groundwork to make significant strides in our understanding of molecular pharmacology in the cancer field.

scholarly journals Proteomic Resistance Biomarkers for PI3K Inhibitor in Triple Negative Breast Cancer Patient-Derived Xenograft Models

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3857
Author(s):  
Zhanfang Guo ◽  
Tina Primeau ◽  
Jingqin Luo ◽  
Cynthia Zhang ◽  
Hua Sun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Triple Negative Breast Cancer ◽  
Growth Response ◽  
Triple Negative ◽  
Pi3k Pathway ◽  
Pi3k Inhibitor ◽  
Pi3k Inhibitors ◽  
Patient Derived Xenograft ◽  
Phosphorylated Akt

PI3K pathway activation is frequently observed in triple negative breast cancer (TNBC). However, single agent PI3K inhibitors have shown limited anti-tumor activity. To investigate biomarkers of response and resistance mechanisms, we tested 17 TNBC patient-derived xenograft (PDX) models representing diverse genomic backgrounds and varying degrees of PI3K pathway signaling activities for their tumor growth response to the pan-PI3K inhibitor, BKM120. Baseline and post-treatment PDX tumors were subjected to reverse phase protein array (RPPA) to identify protein markers associated with tumor growth response. While BKM120 consistently reduced PI3K pathway activity, as demonstrated by reduced levels of phosphorylated AKT, percentage tumor growth inhibition (%TGI) ranged from 35% in the least sensitive to 84% in the most sensitive model. Several biomarkers showed significant association with resistance, including elevated baseline levels of growth factor receptors (EGFR, pHER3 Y1197), PI3Kp85 regulatory subunit, anti-apoptotic protein BclXL, EMT (Vimentin, MMP9, IntegrinaV), NFKB pathway (IkappaB, RANKL), and intracellular signaling molecules including Caveolin, CBP, and KLF4, as well as treatment-induced increases in the levels of phosphorylated forms of Aurora kinases. Interestingly, increased AKT phosphorylation or PTEN loss at baseline were not significantly correlated to %TGI. These results provide important insights into biomarker development for PI3K inhibitors in TNBC.

scholarly journals Mechanisms of Resistance to PI3K Inhibitors in Cancer: Adaptive Responses, Drug Tolerance and Cellular Plasticity

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1538
Author(s):  
Sarah Christine Elisabeth Wright ◽  
Natali Vasilevski ◽  
Violeta Serra ◽  
Jordi Rodon ◽  
Pieter Johan Adam Eichhorn
Keyword(s):  
Tumour Progression ◽  
Therapy Resistance ◽  
Pi3k Pathway ◽  
Cellular Growth ◽  
Cellular Plasticity ◽  
Adaptive Responses ◽  
Mechanisms Of Resistance ◽  
Compensatory Mechanisms ◽  
Pi3k Inhibitors ◽  
Inhibitor Resistance

The phosphatidylinositol-3-kinase (PI3K) pathway plays a central role in the regulation of several signalling cascades which regulate biological processes such as cellular growth, survival, proliferation, motility and angiogenesis. The hyperactivation of this pathway is linked to tumour progression and is one of the most common events in human cancers. Additionally, aberrant activation of the PI3K pathway has been demonstrated to limit the effectiveness of a number of anti-tumour agents paving the way for the development and implementation of PI3K inhibitors in the clinic. However, the overall effectiveness of these compounds has been greatly limited by inadequate target engagement due to reactivation of the pathway by compensatory mechanisms. Herein, we review the common adaptive responses that lead to reactivation of the PI3K pathway, therapy resistance and potential strategies to overcome these mechanisms of resistance. Furthermore, we highlight the potential role in changes in cellular plasticity and PI3K inhibitor resistance.

scholarly journals Interleukin-6 mediates resistance to PI3K-pathway–targeted therapy in lymphoma

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Joo Hyun Kim ◽  
Won Seog Kim ◽  
Chaehwa Park
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Pi3k Pathway ◽  
Resistant Cell ◽  
Pi3k Inhibitor ◽  
Jak Inhibitor ◽  
Pi3k Inhibitors ◽  
Phosphorylated Stat3

Abstract Background The phosphoinositol 3-kinase (PI3K) pathway is associated with poor prognosis of hematologic malignancies, providing a strong rationale for the use of PI3K inhibitors in the treatment of malignant lymphoma. However, development of resistance limits the use of PI3K inhibitors in lymphoma patients. Methods We established copanlisib (pan-PI3K inhibitor)-resistant B-cell lymphoma and duvelisib (PI3Kδ and -γ inhibitor)-resistant T-cell lymphoma cell lines. The cytokine array and the phospho-kinase array were used to identify up-regulated proteins in the resistant cells. Cytokine expression and phospho-kinase levels were examined by ELISA and Western blot analysis, respectively. Cell proliferation capabilities were measured by using CCK-8 kit and colony formation assay. The effects of inhibitors on apoptosis were detected using an Annexin V-FITC Apoptosis Detection Kit and a flow cytometry system. The underlying mechanisms were studied by transfecting recombinant plasmids or siRNA into lymphoma cell lines. Cells were transiently transfected using the Amaxa electroporation system. We evaluated the effects of PI3K inhibitor alone and in combination with JAK inhibitor (BSK805) on lymphoma proliferation and signaling pathway activation. Results Cytokine arrays revealed upregulation of interleukin (IL)-6 in both copanlisib- and duvelisib-resistant cell lines. Phosphorylated STAT5, AKT, p70S6K and MAPK were increased in copanlisib-resistant B-cell lymphoma cells, whereas phosphorylated STAT3 and NF-κB were increased in duvelisib-resistant T cell lymphoma cells. Conversely, depletion of IL-6 sensitized both resistant cell lines, and led to downregulation of phosphorylated STAT3 and STAT5 in copanlisib- and duvelisib-resistant cells, respectively. Moreover, combined treatment with a JAK inhibitor (BSK805) and a PI3K inhibitor circumvented the acquired resistance to PI3K inhibitors in lymphoma, and concurrent inhibition of the activated pathways produced combined effects. Conclusions IL-6–induced STAT3 or STAT5 activation is a critical mechanism underlying PI3K inhibitor resistance in lymphoma, supporting the utility of IL-6 as an effective biomarker to predict therapeutic response to PI3K inhibitors.

3D Culture Modelling: An Emerging Approach for Translational Cancer Research in Sarcomas

2020 ◽  
Vol 27 (29) ◽  
pp. 4778-4788 ◽  
Author(s):  
Victoria Heredia-Soto ◽  
Andrés Redondo ◽  
José Juan Pozo Kreilinger ◽  
Virginia Martínez-Marín ◽  
Alberto Berjón ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Cancer Biology ◽  
Soft Tissues ◽  
Three Dimensional ◽  
3D Culture ◽  
Resistance Mechanisms ◽  
In Vitro Models ◽  
Tumour Spheroids ◽  
Current Therapies

Sarcomas are tumours of mesenchymal origin, which can arise in bone or soft tissues. They are rare but frequently quite aggressive and with a poor outcome. New approaches are needed to characterise these tumours and their resistance mechanisms to current therapies, responsible for tumour recurrence and treatment failure. This review is focused on the potential of three-dimensional (3D) in vitro models, including multicellular tumour spheroids (MCTS) and organoids, and the latest data about their utility for the study on important properties for tumour development. The use of spheroids as a particularly valuable alternative for compound high throughput screening (HTS) in different areas of cancer biology is also discussed, which enables the identification of new therapeutic opportunities in commonly resistant tumours.

scholarly journals PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects

2021 ◽  
Vol 22 (7) ◽  
pp. 3464
Author(s):  
Rosalin Mishra ◽  
Hima Patel ◽  
Samar Alanazi ◽  
Mary Kate Kilroy ◽  
Joan T. Garrett
Keyword(s):  
Clinical Trials ◽  
Intracellular Signaling ◽  
Pi3k Pathway ◽  
Combination Therapies ◽  
Intracellular Signaling Pathway ◽  
Pi3k Inhibitors ◽  
Promising Therapeutic Target ◽  
Cancer Cell Survival ◽  
Current Therapies ◽  
Cancer Types

The phospatidylinositol-3 kinase (PI3K) pathway is a crucial intracellular signaling pathway which is mutated or amplified in a wide variety of cancers including breast, gastric, ovarian, colorectal, prostate, glioblastoma and endometrial cancers. PI3K signaling plays an important role in cancer cell survival, angiogenesis and metastasis, making it a promising therapeutic target. There are several ongoing and completed clinical trials involving PI3K inhibitors (pan, isoform-specific and dual PI3K/mTOR) with the goal to find efficient PI3K inhibitors that could overcome resistance to current therapies. This review focuses on the current landscape of various PI3K inhibitors either as monotherapy or in combination therapies and the treatment outcomes involved in various phases of clinical trials in different cancer types. There is a discussion of the drug-related toxicities, challenges associated with these PI3K inhibitors and the adverse events leading to treatment failure. In addition, novel PI3K drugs that have potential to be translated in the clinic are highlighted.

scholarly journals FGFR Inhibitors in Oncology: Insight on the Management of Toxicities in Clinical Practice

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2968
Author(s):  
Anuhya Kommalapati ◽  
Sri Harsha Tella ◽  
Mitesh Borad ◽  
Milind Javle ◽  
Amit Mahipal
Keyword(s):  
Clinical Utility ◽  
Fibroblast Growth Factor Receptor ◽  
Treatment Guidelines ◽  
Growth Factor Receptor ◽  
The United States ◽  
Resistance Mechanisms ◽  
Effective Management ◽  
Metastatic Urothelial Carcinoma ◽  
Accelerated Approval ◽  
Inhibitor Resistance

Fibroblast Growth Factor receptor (FGFR) pathway aberrations have been implicated in approximately 7% of the malignancies. As our knowledge of FGFR aberrations in cancer continues to evolve, FGFR inhibitors emerged as potential targeted therapeutic agents. The promising results of pemigatinib and infigratinib in advanced unresectable cholangiocarcinoma harboring FGFR2 fusions or rearrangement, and erdafitinib in metastatic urothelial carcinoma with FGFR2 and FGFR3 genetic aberrations, lead to their accelerated approval by the United States (USA) FDA. Along with these agents, many phase II/III clinical trials are currently evaluating the use of derazantinib, infigratinib, and futibatinib either alone or in combination with immunotherapy. Despite the encouraging results seen with FGFR inhibitors, resistance mechanisms and side effect profile may limit their clinical utility. A better understanding of the unique FGFR-inhibitor-related toxicities would invariably help us in the prevention and effective management of FGFR-inhibitor-induced adverse events thereby enhancing their clinical benefit. Herein, we summarized the physiology of FGF/FGFR signaling and briefly discussed the possible mechanisms that could lead to FGFR inhibitor resistance and side effects. In addition, we proposed treatment guidelines for the management of FGFR-inhibitor-associated toxicities. This work would invariably help practicing oncologists to effectively manage the unique toxicities of FGFR inhibitors.

Distribution of PPX2 Mutations Conferring PPO-Inhibitor Resistance in Palmer Amaranth Populations of Tennessee

2018 ◽  
Vol 32 (5) ◽  
pp. 592-596 ◽  
Author(s):  
J. Drake Copeland ◽  
Darci A. Giacomini ◽  
Patrick J. Tranel ◽  
Garret B. Montgomery ◽  
Lawrence E. Steckel
Keyword(s):  
Resistance Mechanisms ◽  
Palmer Amaranth ◽  
The Other ◽  
Group 14 ◽  
Row Crops ◽  
Site Of Action ◽  
Inhibitor Resistance ◽  
New Mutations

AbstractProtoporphyrinogen IX oxidase (PPO)–inhibiting herbicides (WSSA Group 14) have been used in agronomic row crops for over 50 yr. Broadleaf weeds, including glyphosate-resistant Palmer amaranth, have been controlled by this herbicide site of action PRE and POST. Recently, Palmer amaranth populations were reported resistant to PPO inhibitors in 2011 in Arkansas, in 2015 in Tennessee, and in 2016 in Illinois. Historically, the mechanism for this resistance involves the deletion of a glycine at position 210 (ΔG210) in a PPO enzyme encoded by the PPX2 gene; however, the ΔG210 deletion did not explain all PPO inhibitor–resistant Palmer amaranth in Tennessee populations. Recently, two new mutations within PPX2 (R128G, R128M) that confer resistance to PPO inhibitors were identified in Palmer amaranth. Therefore, research is needed to document the presence and distribution of the three known mutations that confer PPO inhibitor resistance in Tennessee. In 2017, a survey was conducted in 18 fields with Palmer amaranth to determine whether resistance existed and the prevalence of each known mutation in each field. Fomesafen was applied at 265 g ai ha–1 to Palmer amaranth infestations within each field to select for resistant weeds for later analysis. Where resistance was described (70% of surviving plants), the ΔG210 mutation was detected in 47% of resistant plants. The R128G mutation accounted for 42% of resistance, similar to the frequency of the ΔG210 mutation. The R128M mutation was less frequent than the other two mutations, accounting for only 10% of the resistance. All mutations detected in this study were heterozygous. Additionally, no more than one of the three PPX2 mutations were detected in an individual surviving plant. Similar to previous research, about 70% of PPO resistance was accounted for by these three known mutations, leaving about 30% of resistance not characterized in Tennessee populations. Survivors not showing the three known PPO mutations suggest that other resistance mechanisms are present.

scholarly journals PI3K in Stemness Regulation: From Development to Cancer

2019 ◽  
Author(s):  
Ralitsa Madsen
Keyword(s):  
Stem Cell ◽  
Pluripotent Stem Cells ◽  
Cancer Biology ◽  
Pi3k Pathway ◽  
Dependent Manner ◽  
Pten Loss ◽  
Pi3k Activation ◽  
Developmental Signalling ◽  
Dose Dependent

The PI3K/AKT pathway is a key target in oncology where most efforts are focussed on phenotypes such as cell proliferation and survival. Comparatively little attention has been paid to PI3K in stemness regulation, despite the emerging link between acquisition of stem cell-like features and therapeutic failure in cancer. The aim of this review is to summarise current known and unknowns of PI3K-dependent stemness regulation, by integrating knowledge from the fields of developmental, signalling and cancer biology. Particular attention is given to the role of the PI3K pathway in pluripotent stem cells (PSCs) and the emerging parallels to dedifferentiated cancer cells with stem cell-like features. Compelling evidence suggests that PI3K/AKT signalling forms part of a ‘core molecular stemness programme’ in both mouse and human PSCs. In cancer, the oncogenic PIK3CAH1047R variant causes constitutive activation of the PI3K pathway and has recently been linked to increased stemness in a dose-dependent manner, similar to observations in mouse PSCs with heterozygous versus homozygous Pten loss. There is also evidence that the stemness phenotype may become ‘locked’ and thus independent of the original PI3K activation, posing limitations for the success of PI3K monotherapy in cancer.Ongoing therapeutic developments for PI3K-associated cancers may therefore benefit from a better understanding of the pathway’s two-layered and highly context-dependent regulation of cell growth versus stemness.

Sign in / Sign up

Export Citation Format

Share Document