PI3K pathway activation results in low efficacy of both trastuzumab and lapatinib

Wang, Leiping; Zhang, Qunling; Zhang, Jian; Sun, Si; Guo, Haiyi; Jia, Zhen; Wang, Biyun; Shao, Zhimin; Wang, Zhonghua; Hu, Xichun

doi:10.1186/1471-2407-11-248

Cited by 131 publications

(91 citation statements)

References 56 publications

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“…Compared with Caucasians, breast cancer in Oriental populations is a heterogeneous disease with divergent molecular mechanisms of pathogenesis. One study (Wang et al, 2011) also found a lower PIK3CA mutation rate (12.3%) in Chinese breast cancers. In addition, of the PIK3CA mutations detected in our study, 44.44% were E542K mutations, 33.33% were E545K, and 22.22% were H1047R; no mutations of other sites were found.…”

Section: Discussionmentioning

confidence: 90%

Mutational Analysis of Key EGFR Pathway Genes in Chinese Breast Cancer Patients

Lin

Yang²,

Liu³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Background: The epidermal growth factor receptor (EGFR) is a potential therapeutic target for breast cancer treatment; however, its use does not lead to a marked clinical response. Studies of non-small cell lung cancer and colorectal cancer showed that mutations of genes in the PIK3CA/AKT and RAS/RAF/MEK pathways, two major signalling cascades downstream of EGFR, might predict resistance to EGFR-targeted agents. Therefore, we examined the frequencies of mutations in these key EGFR pathway genes in Chinese breast cancer patients. Methods: We used a high-throughput mass-spectrometric based cancer gene mutation profiling platform to detect 22 mutations of the PIK3CA, AKT1, BRAF, EGFR, HRAS, and KRAS genes in 120 Chinese women with breast cancer. Results: Thirteen mutations were detected in 12 (10%) of the samples, all of which were invasive ductal carcinomas (two stage I, six stage II, three stage III, and one stage IV). These included one mutation (0.83%) in the EGFR gene (rs121913445-rs121913432), three (2.50%) in the KRAS gene (rs121913530, rs112445441), and nine (7.50%) in the PIK3CA gene (rs121913273, rs104886003, and rs121913279). No mutations were found in the AKT1, BRAF, and HRAS genes. Six (27.27%) of the 22 genotyping assays called mutations in at least one sample and three (50%) of the six assays queried were found to be mutated more than once. Conclusions: Mutations in the EGFR pathway occurred in a small fraction of Chinese breast cancers. However, therapeutics targeting these potential predictive markers should be investigated in depth, especially in Oriental populations.

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Section: Discussionmentioning

confidence: 90%

Mutational Analysis of Key EGFR Pathway Genes in Chinese Breast Cancer Patients

Lin

Yang²,

Liu³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…Loss of PTEN in BT474 cells by shRNAs was shown to lead to lapatinib resistance both in vitro and in vivo [25]. Similarly, activation of PI3K signaling resulting from PTEN loss or PI3K mutations has been reported for both trastuzumab and lapatinib resistance in patients [26]. On the other hand, the response to lapatinib of ErbB2-overexpressing PTEN-knockdown BT474 and AU565 cell lines, and of patients with inflammatory breast cancers is independent of PTEN status [27].…”

Section: Discussionmentioning

confidence: 95%

Biomarker-guided sequential targeted therapies to overcome therapy resistance in rapidly evolving highly aggressive mammary tumors

et al. 2014

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Combinatorial targeted therapies are more effective in treating cancer by blocking by-pass mechanisms or inducing synthetic lethality. However, their clinical application is hampered by resistance and toxicity. To meet this important challenge, we developed and tested a novel concept of biomarker-guided sequential applications of various targeted therapies using ErbB2-overexpressing/PTEN-low, highly aggressive breast cancer as our model. Strikingly, sustained activation of ErbB2 and downstream pathways drives trastuzumab resistance in both PTEN-low/ trastuzumab-resistant breast cancers from patients and mammary tumors with intratumoral heterogeneity from genetically-engineered mice. Although lapatinib initially inhibited trastuzumab-resistant mouse tumors, tumors bypassed the inhibition by activating the PI3K/mTOR signaling network as shown by the quantitative protein arrays. Interestingly, activation of the mTOR pathway was also observed in neoadjuvant lapatinib-treated patients manifesting lapatinib resistance. Trastuzumab + lapatinib resistance was effectively overcome by sequential application of a PI3K/mTOR dual kinase inhibitor (BEZ235) with no significant toxicity. However, our p-RTK array analysis demonstrated that BEZ235 treatment led to increased ErbB2 expression and phosphorylation in genetically-engineered mouse tumors and in 3-D, but not 2-D, culture, leading to BEZ235 resistance. Mechanistically, we identified ErbB2 protein stabilization and activation as a novel mechanism of BEZ235 resistance, which was reversed by subsequent treatment with lapatinib + BEZ235 combination. Remarkably, this sequential application of targeted therapies guided by biomarker changes in the tumors rapidly evolving resistance doubled the life-span of mice bearing exceedingly aggressive tumors. This fundamentally novel approach of using targeted therapies in a sequential order can effectively target and reprogram the signaling networks in cancers evolving resistance during treatment.

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“…Genetic alterations in the PI3K pathway are also implicated in reduced response to lapatinib treatment. 10 Methylation changes in CpG islands (CGI) and CpG shores (low CpG density areas ~2 Kb close to CGI) affect gene expression. 11 In addition to such local changes, global hypomethylation and chromosomal instabilities have been found in cancers.…”

Section: Introductionmentioning

confidence: 99%