Anticipating mechanisms of resistance to PI3K inhibition in breast cancer: a challenge in the era of precision medicine

2014 ◽  
Vol 42 (4) ◽  
pp. 733-741 ◽  
Author(s):  
Cedric Leroy ◽  
Romain J. Amante ◽  
Mohamed Bentires-Alj
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Pik3ca Mutation ◽  
Mechanisms Of Resistance ◽  
Combination Treatments ◽  
Development Of Resistance ◽  
Pi3k Inhibition ◽  
Pi3k Signalling ◽  
Phosphoinositide 3 Kinase

Frequent subversion of the PI3K (phosphoinositide 3-kinase) pathway during neoplastic transformation contributes to several hallmarks of cancer that result in a competitive advantage for cancer cells. Deregulation of this pathway can be the result of genomic alterations such as PIK3CA mutation, PTEN (phosphatase and tensin homologue deleted on chromosome 10) loss or the activation of upstream protein tyrosine kinases. Not surprisingly, the PI3K signalling pathway has become an attractive therapeutic target, and numerous inhibitors are in clinical trials. Unfortunately, current therapies for advanced cancers that target PI3K often lead to the development of resistance and relapse of the disease. It is therefore important to establish the molecular mechanisms of resistance to PI3K-targeted therapy. With the focus on breast cancer, in the present article, we summarize the different ways of targeting PI3K, review potential mechanisms of resistance to PI3K inhibition and discuss the rationale of combination treatments to reach a balance between efficacy and toxicity.

Buparlisib in Kombination mit Tamoxifen: Rationale für zielgerichtete Therapie bei PIK3CA-mutiertem metastasierten Mammakarzinom bestätigt

2021 ◽  
pp. 1-3
Author(s):  
Carlota Claussen ◽  
Maggie Banys-Paluchowski
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Pik3ca Mutation ◽  
Progression Free Survival ◽  
Breast Cancer Patients ◽  
Serum Samples ◽  
Open Label ◽  
Pik3ca Mutations ◽  
Hormone Receptor Positive ◽  
Pi3k Inhibition

The PIKTAM study evaluated the efficacy and safety of the PI3K inhibitor buparlisib in combination with tamoxifen in hormone receptor-positive (HR+), HER2-negative advanced breast cancer patients after failure of prior endocrine therapy. In this open-label, single-arm phase II trial, 25 patients were enrolled in 11 sites in Germany. Patients were stratified according to PIK3CA mutation status (tissue and cfDNA from serum samples) and/or loss of PTEN expression. Patients received buparlisib (100mg) and tamoxifen (20mg) once daily on a continuous schedule (28-day cycle) until progression or unacceptable toxicity. Primary endpoint was overall 6-month progression-free survival (PFS) rate. Key secondary endpoints included the 6-month PFS rate in subpopulations, PFS, overall survival, overall response rate (ORR), disease control rate (DCR), and safety. Overall, the 6-month PFS rate was 33.3% (n/N = 7/21, one-sided 95% CI 16.8–100) and median PFS was 6.1 (CI 2.6–10.6) months. The ORR and DCR were 12.5% and 44%. The PIK3CA-mutated subgroup consistently showed the highest 6-month PFS rate (62.5%, n/N = 5/8), median PFS (8.7 months), ORR (40%), and DCR (80%). No new safety signals emerged. Most common adverse events were gastrointestinal disorders (56%), psychiatric/mood disorders (48%), skin rash/hypersensitivity (44%), cardiovascular (40%), and hepatic (32%) events. The trial was prematurely terminated due to the substantially altered risk – benefit profile of buparlisib. Nevertheless, PIK3CA mutations emerged as a clinically feasible and useful biomarker for combined PI3K inhibition and endocrine therapy in patients with HR+ breast cancer. Further biomarker – stratified studies with isoform – specific PI3K inhibitors are warranted. EudraCT No: 2014–000599–24.

Predictive factors of resistance to trastuzumab as neoadjuvant therapy in women with HER2-positive breast cancer.

2013 ◽  
Vol 31 (26_suppl) ◽  
pp. 168-168
Author(s):  
Hiromitsu Jinno ◽  
Tomomi Sato ◽  
Maiko Takahashi ◽  
Tetsu Hayashida ◽  
Shigemichi Hirose ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Therapy ◽  
Hormone Receptor ◽  
Direct Sequencing ◽  
Pik3ca Mutation ◽  
Operable Breast Cancer ◽  
Mechanisms Of Resistance ◽  
Her2 Positive ◽  
Pten Loss ◽  
Hormone Receptor Positive

168 Background: Despite clinical usefulness of trastuzumab, intrinsic or acquired resistance to trastuzumab is a common clinical phenomenon. However, the mechanisms of resistance to trastuzumab have not been fully elucidated. The objective of this study was to determine the possible mechanisms of resistance to trastuzumab as neoadjuvant therapy in women with HER2-overexpressing operable breast cancer. Methods: Patients with operable breast cancer received 12 cycles of weekly paclitaxel plus weekly trastuzumab before surgery. All tumors were HER2-positive by immunohistochemistry (IHC) or fluorescence in situ hybridization. Expressions of ER, PgR, Ki67, PTEN, phosphorylated IGF-1R (pIGF-1R) and MUC4 were performed by IHC in core needle biopsy samples at baseline. PIK3CA mutation status was evaluated by sequencing of PIK3CA exons 9 and 20 using PCR amplification and direct sequencing. Results: Thirty-seven patients were enrolled and assessable for clinical and pathologic responses. The pCR rate was 48.6% (18/37). Negative, moderate and strong membranous expression of MUC4 was observed in 3 (8.1%), 18 (48.6%) and 12 (32.4%) patients, respectively. Membranous staining for pIGF1-R was negative in 24 (64.9%) patients. PTEN loss was observed in 33.3% (8/24) of the tumor examined. PIK3CA sequence analysis of the 13 tumors identified 2 mutations in exon 20 and 2 mutations in exon 9, corresponding to a PIK3CA mutation frequency of 30.8%. MUC4 status did not affect the pCR rate. Although membranous pIGF1-R expression did not affect pCR rate in hormone receptor-positive patients (66.7% vs. 50.0%), hormone receptor-positive patients with positive membranous pIGF1-R tended to show higher pCR rate compared with negative pIGF1-R (41.2% vs. 0%). PTEN loss and/or PIK3CA mutation were not significantly associated with pCR rate. Conclusions: These data indicate that aberrant downstream signaling caused by loss of PTEN and/or PIK3CA mutation, alternative signaling from IGF-1R and masking with MUC4 were not important mechanisms of resistance to trastuzumab.

scholarly journals Carboplatin: molecular mechanisms of action associated with chemoresistance

2014 ◽  
Vol 50 (4) ◽  
pp. 693-701 ◽  
Author(s):  
Graziele Fonseca de Sousa ◽  
Samarina Rodrigues Wlodarczyk ◽  
Gisele Monteiro
Keyword(s):  
Molecular Mechanisms ◽  
Therapeutic Strategies ◽  
Mechanisms Of Action ◽  
Rational Drug Design ◽  
Full Potential ◽  
Mechanisms Of Resistance ◽  
Development Of Resistance ◽  
Rational Drug ◽  
Biochemical Mechanisms ◽  
Tumor Types

Carboplatin is a derivative of cisplatin; it has a similar mechanism of action, but differs in terms of structure and toxicity. It was approved by the FDA in the 1980s and since then it has been widely used in the treatment of several tumor types. This agent is characterized by its ability to generate lesions in DNA through the formation of adducts with platinum, thereby inhibiting replication and transcription and leading to cell death. However, its use can lead to serious inconvenience arising from the development of resistance that some patients acquire during treatment, limiting the scope of its full potential. Currently, the biochemical mechanisms related to resistance are not precisely known. Therefore, knowledge of pathways associated with resistance caused by carboplatin exposure may provide valuable clues for more efficient rational drug design in platinum-based therapy and the development of new therapeutic strategies. In this narrative review, we discuss some of the known mechanisms of resistance to platinum-based drugs, especially carboplatin.

scholarly journals Induction of Paraptotic Cell Death in Breast Cancer Cells by a Novel Pyrazolo[3,4-h]quinoline Derivative through ROS Production and Endoplasmic Reticulum Stress

Antioxidants ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 117
Author(s):  
Phuong Linh Nguyen ◽  
Chang Hoon Lee ◽  
Heesoon Lee ◽  
Jungsook Cho
Keyword(s):  
Breast Cancer ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Quinoline Derivative ◽  
Ros Generation ◽  
Protein Accumulation ◽  
Potential Candidate ◽  
Development Of Resistance

Chemotherapy has been a standard intervention for a variety of cancers to impede tumor growth, mainly by inducing apoptosis. However, development of resistance to this regimen has led to a growing interest and demand for drugs targeting alternative cell death modes, such as paraptosis. Here, we designed and synthesized a novel derivative of a pyrazolo[3,4-h]quinoline scaffold (YRL1091), evaluated its cytotoxic effect, and elucidated the underlying molecular mechanisms of cell death in MDA-MB-231 and MCF-7 breast cancer (BC) cells. We found that YRL1091 induced cytotoxicity in these cells with numerous cytoplasmic vacuoles, one of the distinct characteristics of paraptosis. YRL1091-treated BC cells displayed several other distinguishing features of paraptosis, excluding autophagy or apoptosis. Briefly, YRL1091-induced cell death was associated with upregulation of microtubule-associated protein 1 light chain 3B, downregulation of multifunctional adapter protein Alix, and activation of extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase. Furthermore, the production of reactive oxygen species (ROS) and newly synthesized proteins were also observed, subsequently causing ubiquitinated protein accumulation and endoplasmic reticulum (ER) stress. Collectively, these results indicate that YRL1091 induces paraptosis in BC cells through ROS generation and ER stress. Therefore, YRL1091 can serve as a potential candidate for the development of a novel anticancer drug triggering paraptosis, which may provide benefit for the treatment of cancers resistant to conventional chemotherapy.

scholarly journals Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review

2019 ◽  
Vol 145 (5) ◽  
pp. 1179-1188 ◽  
Author(s):  
Kamal Pandey ◽  
Hee‐Jung An ◽  
Seung Ki Kim ◽  
Seung Ah Lee ◽  
Sewha Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Mechanisms ◽  
Mechanisms Of Resistance

scholarly journals Molecular mechanisms of resistance to monoclonal antibodies therapy patients with squamous cell carcinoma of the tongue and mucosa of the oral cavity

2019 ◽  
Vol 8 (4) ◽  
pp. 13-25
Author(s):  
L. Yu. Vladimirova ◽  
A. A. Lyanova ◽  
E. M. Frantsiyants ◽  
D. S. Kutilin ◽  
M. A. Engibaryan
Keyword(s):  
Monoclonal Antibodies ◽  
Oral Cavity ◽  
Cell Carcinoma ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Current Data ◽  
Mechanisms Of Resistance ◽  
Mesenchymal Transition ◽  
Carcinoma Of The Tongue

The review analyzes current data on the molecular mechanisms of resistance to monoclonal antibodies in patients withsquamous cell carcinoma of the tongue and mucosa of the oral cavity. The mechanisms of resistance to monoclonal anti-ERBBand anti-PD1 antibodies and ways to overcome it are described in detail. The analysis made it possible to identify a number of factorsthat should be taken into account when assigning therapy with monoclonal antibodies: activation of alternative receptor tyrosinekinases, increased expression of receptor ligand genes, mutations in effectors and the receptor tyrosine kinases themselves, disruptionof the formation of functional receptor dimers, changes in proteins and coding for them genes responsible for the regulation ofcascades of apoptosis, mitosis, epithelial-mesenchymal transition, secretion of anti-inflammatory cytokines and immunosuppressivemetabolites.

Mechanisms of resistance to trastuzumab as neoadjuvant therapy in women with HER2-overexpressing operable breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e11060-e11060
Author(s):  
Hiromitsu Jinno ◽  
Tomomi Sato ◽  
Tetsu Hayashida ◽  
Maiko Takahashi ◽  
Shigemichi Hirose ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Direct Sequencing ◽  
Pik3ca Mutation ◽  
Acquired Resistance ◽  
Pcr Amplification ◽  
Operable Breast Cancer ◽  
Mechanisms Of Resistance ◽  
Her2 Positive ◽  
Pten Loss ◽  
Downstream Signaling

e11060 Background: Despite clinical usefulness of trastuzumab, intrinsic or acquired resistance is a common clinical phenomenon. Potential mechanisms of resistance include aberrant downstream signaling caused by loss of PTEN and/or PIK3CA mutation, alternative signaling from IGF-1R and masking with MUC4. Methods: Patients with operable breast cancer received 12 cycles of weekly paclitaxel (80 mg/m2 IV) plus weekly trastuzumab (4mg/kg loading dose followed by 2 mg/kg IV) before surgery. All tumors were HER2-positive by immunohistochemistry (IHC) or fluorescence in situ hybridization. Expressions of ER, PgR, Ki67, PTEN, phosphorylated IGF-1R (pIGF-1R) and MUC4 were performed by IHC in core needle biopsy samples at baseline. ER and PgR status was assessed using Allred score. For Ki67 labeling index, a total of 400 cells were counted from three consecutive high-power magnifications. PTEN, pIGF-1R and MUC4 expression level was scored semiquantitatively based on staining intensity. PIK3CA mutation status was evaluated by sequencing of PIK3CA exons 9 and 20 using PCR amplification and direct sequencing. Results: Thirty-seven patients were enrolled and assessable for clinical and pathologic responses. The pCR rate was 48.6% (18/37). ER and PgR were positive in 18 (48.6%) and 16 (43.2%) patients, respectively. Negative, moderate and strong membranous expression of MUC4 was observed in 3 (8.1%), 18 (48.6%) and 12 (32.4%) patients, respectively. Membranous staining for pIGF1-R was negative in 24 (64.9%) patients. PTEN loss was observed in 33.3% (8/24) of the tumor examined. PIK3CA sequence analysis of the 13 tumors identified 2 mutations in exon 20 and 2 mutations in exon 9, corresponding to a PIK3CA mutation frequency of 30.8%. MUC4 and pIGF1-R status did not affect the pCR rate. PTEN loss and/or PIK3CA mutation were not significantly associated with pCR rate. pCR rate was significantly correlated with PgR negativity (p=0.004) and higher Ki67 (p=0.01). Conclusions: These data indicate that aberrant downstream signaling caused by loss of PTEN and/or PIK3CA mutation, alternative signaling from IGF-1R and masking with MUC4 were not important mechanisms of resistance to trastuzumab.

scholarly journals Cisplatin-resistant triple-negative breast cancer subtypes: multiple mechanisms of resistance

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
David P. Hill ◽  
Akeena Harper ◽  
Joan Malcolm ◽  
Monica S. McAndrews ◽  
Susan M. Mockus ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Treatment Strategies ◽  
Heterogeneous Data ◽  
Variable Response ◽  
Mechanisms Of Resistance ◽  
Mesenchymal Transition ◽  
Cancer Subtypes

Abstract Background Understanding mechanisms underlying specific chemotherapeutic responses in subtypes of cancer may improve identification of treatment strategies most likely to benefit particular patients. For example, triple-negative breast cancer (TNBC) patients have variable response to the chemotherapeutic agent cisplatin. Understanding the basis of treatment response in cancer subtypes will lead to more informed decisions about selection of treatment strategies. Methods In this study we used an integrative functional genomics approach to investigate the molecular mechanisms underlying known cisplatin-response differences among subtypes of TNBC. To identify changes in gene expression that could explain mechanisms of resistance, we examined 102 evolutionarily conserved cisplatin-associated genes, evaluating their differential expression in the cisplatin-sensitive, basal-like 1 (BL1) and basal-like 2 (BL2) subtypes, and the two cisplatin-resistant, luminal androgen receptor (LAR) and mesenchymal (M) subtypes of TNBC. Results We found 20 genes that were differentially expressed in at least one subtype. Fifteen of the 20 genes are associated with cell death and are distributed among all TNBC subtypes. The less cisplatin-responsive LAR and M TNBC subtypes show different regulation of 13 genes compared to the more sensitive BL1 and BL2 subtypes. These 13 genes identify a variety of cisplatin-resistance mechanisms including increased transport and detoxification of cisplatin, and mis-regulation of the epithelial to mesenchymal transition. Conclusions We identified gene signatures in resistant TNBC subtypes indicative of mechanisms of cisplatin. Our results indicate that response to cisplatin in TNBC has a complex foundation based on impact of treatment on distinct cellular pathways. We find that examination of expression data in the context of heterogeneous data such as drug-gene interactions leads to a better understanding of mechanisms at work in cancer therapy response.

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