Direct Inhibition of PI3K in Combination with Dual HER2 Inhibitors is Required for Optimal Antitumor Activity in HER2+ Breast Cancer Cells

Rexer, Brent N.; Chanthaphaychith, Siprachanh; Dahlman, Kimberly B.; Arteaga, Carlos L.

doi:10.1201/b17138-4

Cited by 17 publications

(21 citation statements)

References 37 publications

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“…PIK3CA gene mutations acquired during disease progression are likely to relect increased activation of the PI3K pathway and therefore suggest possible implications in resistance [47]. Consistently with this hypothesis, in vitro data show that ErbB2 gene ampliication and PI3KCA gene mutations are associated with resistance to ErbB2-targeted agents [49,62,63] and PTEN loss or PIK3CA gene mutations have been linked to resistance to ErbB2 targeted therapy [48]. Since the serine/threonine kinase mTOR represents the inal sensor of the ErbB2-dependent activation of the PI3K/AKT pathway and it is negatively regulated by PTEN, it is conceivable that targeting mTOR might be more eicacious than targeting multiple pathways with diferent strategies [48,64] to interfere with tumor progression and to prevent resistance to ErbB2-targeted therapy.…”

Section: Overcoming Resistance To Targeted Therapysupporting

confidence: 69%

ErbB2 Receptor in Breast Cancer: Implications in Cancer Cell Migration, Invasion and Resistance to Targeted Therapy

Camacho-Leal¹,

Sciortino²,

Cabodi³

2017

Breast Cancer - From Biology to Medicine

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Overexpression of ErbB2 is found in several types of human carcinomas. In breast tumors, ErbB2 overexpression is detected in up to 20% of patients. Breast cancers in with ampliication of ErbB2 are characterized by rapid tumor growth, lower survival rate and increased disease progression. The molecular mechanisms underlying the oncogenic action of ErbB2 involve a complex signaling network that tightly regulates malignant cell migration and invasion and hence metastatic potential. Recent eforts have been made to identify gene expression signatures of ErbB2-positive invasive breast cancers that may represent important mediators of ErbB2-induced tumorigenesis and metastatic progression.In this chapter, we will discuss the canonical ErbB2 signaling pathways responsible for tumor growth and dissemination along with newly identiied mediators such as adaptor protein p130Cas and miRNAs. From a therapeutic point of view, the treatment with anti-ErbB2 monoclonal antibody trastuzumab has greatly improved the outcomes of patients with ErbB2 aggressive cancer. Nevertheless, de novo and acquired resistance to trastuzumab therapy still represent a major clinical problem. In the second part of the chapter, we will provide an overview of the mechanisms so far implicated in the onset of resistance to targeted therapy and of the new strategies to overcome resistance.

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Section: Overcoming Resistance To Targeted Therapysupporting

confidence: 69%

ErbB2 Receptor in Breast Cancer: Implications in Cancer Cell Migration, Invasion and Resistance to Targeted Therapy

Camacho-Leal¹,

Sciortino²,

Cabodi³

2017

Breast Cancer - From Biology to Medicine

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“…[4,5] Over-expression of HER-2/neu gene and it's protein are associated breast cancer patient's prognosis and therapy. [4] Trastuzumab (Herceptin®), a recombinant, humanized, monoclonal antibody targeting HER2 is well established as an effective treatment for HER2-positive breast cancer [6,7].…”

Section: Introductionmentioning

confidence: 99%

Comparison of IHC, FISH, ER and PR in Breast Cancer in Western Iran

Payandeh¹,

Sadeghi²,

Sadeghi³

et al. 2014

AJCP

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To evaluate the concordance and discordance between IHC and FISH results for detection of Her2/neu protein, analyses of ER and PR, and also evaluation of the benefit of adjuvant trastuzumab in patients diagnosed with human epidermal growth factor receptor 2 (HER2) -positive invasive ductal carcinoma enrolled onto the Herceptin adjuvant. IHC analysis of ER, PR and HER2 was performed in 133 patients of breast cancer with invasive ductal carcinoma. 90(67.6%) cases were confirmed by FISH. Statistical analysis was performed with IBM SPSS version 19, Kaplan-Meier method and log-rank test. Age mean of patients was 46.39±10.81 years (range, 24-78 years). Concordance rates between IHC and FISH were 32.4% for IHC 2+ and 81.25% for IHC 3+ (P<0.001). There were 17 and 56 patients of IHC 2+ and 3+ with ER positive and also 23 and 59 patients of IHC 2+ and 3+ had PR positive.The 83 patients had age ≤50 years and 50 patients had >50 years. Of 133 the patients, 48(36.1%) patients were treated with trastuzumab and 85(63.9%) were treated without trastuzumab. The overall survival(OS) for patients treating with trastuzumab were mean of 37.8 months and the OS for patients treating without trastuzumab were mean of 20.8 months (P<0.05). The results are that trastuzumab therapy is effective and improves the survival of HER2-positive breast cancer patients and trastuzumab therapy is effective and tolerated for breast cancer with Her-2 positive. There is a statistically significant relationship between ER positive with PR positive and ER negative with PR negative that these results need to more studies with more patients in the world.

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“…Rexer and group elegantly showed that acquisition of a hotspot PIK3CA mutation (either in helical or in kinase domain) is a mechanism of acquired resistance to lapatinib and that PIK3CA mutations partially uncouple PI3K from HER2 to permit the development and maintenance of resistance. Moreover, targeting of PI3K itself, in combination with maximal HER2 blockade with both an antibody and a TKI, is more effective than HER2 targeting alone for HER2+ breast tumors without PIK3CA mutations and this combination is definitely required for HER2+ breast tumors with PIK3CA mutations [85].…”

Section: Activation Of Pten-pi3k-akt-mtor Pathway and Anti-her2 Theramentioning

confidence: 98%

HER2 Signaling Network in Advanced Breast Cancer: Opportunities for Combination Therapies

Dey

Leyland‐Jones

2016

Cancer Drug Discovery and Development

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Direct Inhibition of PI3K in Combination with Dual HER2 Inhibitors is Required for Optimal Antitumor Activity in HER2+ Breast Cancer Cells

Cited by 17 publications

References 37 publications

ErbB2 Receptor in Breast Cancer: Implications in Cancer Cell Migration, Invasion and Resistance to Targeted Therapy

ErbB2 Receptor in Breast Cancer: Implications in Cancer Cell Migration, Invasion and Resistance to Targeted Therapy

Comparison of IHC, FISH, ER and PR in Breast Cancer in Western Iran

HER2 Signaling Network in Advanced Breast Cancer: Opportunities for Combination Therapies

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