CP-724714

CP-724714 is an inhibitor of erbB2 and EGFR kinases with IC50 values of 10±3 nmol/L and 6,400±2,100 nmol/L, respectively [1].

In the in vitro cell cycle assay, CP-724714 cause a G1 block of the Her2-amplified BT-474 breast cancer cells due to its inhibition of erbB2. CP-724714 at 1 mol/L can also reduce the level of phospho-erbB2 in these cells. In in vivo assay, CP-724714 cause a concentration-dependent reduction of tumor erbB2 receptor phosphorylation in athymic mice bearing FRE-erbB2

Xenografts. CP-724714 treatments also resulted in a time- and dose-dependent induction of tumor cell apoptosis. In two human breast carcinoma models, BT-474 and MDA-MB-453, which are Her2 amplified and highly overexpress erbB2, CP-724714 is found to produce a dose-dependent inhibition of xenograft growth. In addition, CP-724,714 treatments induce reduction of downstream erbB2 RTK signaling. On the basis of these, CP-724,714 was advanced to phase I clinical trials and is potentially another option for Her2-driven breast cancer [1].

References:
[1] Jitesh P. Jani, Richard S. Finn, Mary Campbell, et al. Discovery and Pharmacologic Characterization of CP-724714, a Selective ErbB2 Tyrosine Kinase Inhibitor. Cancer Research. 2007 (67): 9887-9893.

Rationale for Using Irreversible Epidermal Growth Factor Receptor Inhibitors in Combination with Phosphatidylinositol 3-Kinase Inhibitors for Advanced Head and Neck Squamous Cell Carcinoma.[Pubmed:30858165]

Mol Pharmacol. 2019 May;95(5):528-536.

Head and neck squamous cell carcinoma (HNSCC) is a common and debilitating form of cancer characterized by poor patient outcomes and low survival rates. In HNSCC, genetic aberrations in phosphatidylinositol 3-kinase (PI3K) and epidermal growth factor receptor (EGFR) pathway genes are common, and small molecules targeting these pathways have shown modest effects as monotherapies in patients. Whereas emerging preclinical data support the combined use of PI3K and EGFR inhibitors in HNSCC, in-human studies have displayed limited clinical success so far. Here, we examined the responses of a large panel of patient-derived HNSCC cell lines to various combinations of PI3K and EGFR inhibitors, including EGFR agents with varying specificity and mechanistic characteristics. We confirmed the efficacy of PI3K and EGFR combination therapies, observing synergy with alpha isoform-selective PI3K inhibitor HS-173 and irreversible EGFR/ERBB2 dual inhibitor afatinib in most models tested. Surprisingly, however, our results demonstrated only modest improvement in response to HS-173 with reversible EGFR inhibitor gefitinib. This difference in efficacy was not explained by differences in ERBB target selectivity between afatinib and gefitinib; despite effectively disrupting ERBB2 phosphorylation, the addition of ERBB2 inhibitor CP-724714 failed to enhance the effect of HS-173 gefitinib dual therapy. Accordingly, although irreversible ERBB inhibitors showed strong synergistic activity with HS-173 in our models, none of the reversible ERBB inhibitors were synergistic in our study. Therefore, our results suggest that the ERBB inhibitor mechanism of action may be critical for enhanced synergy with PI3K inhibitors in HNSCC patients and motivate further preclinical studies for ERBB and PI3K combination therapies.

Store operated calcium entry is altered by the inhibition of receptors tyrosine kinase.[Pubmed:29662626]

Oncotarget. 2018 Mar 23;9(22):16059-16073.

SOCE (Store-Operated Calcium Entry) is the main mechanism by which external Ca(2+) enters into non-excitable cells after endoplasmic reticulum emptying. It is implicated in several processes such as proliferation and migration. Alterations in SOCE could initiate or support the development of hallmarks of cancer. In this project, we showed that disruption of the EGFR/ErbB2-dependent signalling by lapatinib and CP-724714, two inhibitors of the receptor tyrosine kinase (RTK), dramatically reduced the amplitude of the SOCE in breast cancer cells. LY294002 and MK2206, two inhibitors of the PI3K/Akt pathway, mimicked the effect of the inhibition of EGFR/ErbB2. In contrast, inhibitors of the MAPK pathway had no effect on SOCE. The involvement of EGFR/ErbB2 receptors and the PI3K/Akt pathway in the regulation of SOCE was confirmed in other cell lines derived from various cancer types. All these results showed that SOCE is positively regulated by the PI3K/Akt pathway and that this effect may be suppressed by the inhibition of the upstream RTKs. Inhibition of SOCE might therefore contribute to the anticancer effects of RTK inhibitors.

Cooperative oncogenic effect and cell signaling crosstalk of cooccurring HER2 and mutant PIK3CA in mammary epithelial cells.[Pubmed:28902361]

Int J Oncol. 2017 Oct;51(4):1320-1330.

Though incidence of PI3K oncogenic mutation is prominent in breast cancer (20-30%), pharmacological targeting of this signaling pathway alone has failed to provide meaningful clinical benefit. To better understand and address this problem, we conducted genome-wide analysis to study the association of mutant PI3K with other gene amplification events. One of the most significant copy number gain events associated with PIK3CA mutation was the region within chromosome 17 containing HER2. To investigate the oncogenic effect and cell signaling regulation of co-occurring PIK3CA-H1047R and or HER2 gene, we generated cell models ectopically expressing mutant PIK3CA, HER2 or both genetic alterations. We observed that cells with both genetic alterations demonstrate increased aggressiveness and invasive capabilities than cells with either genetic change alone. Furthermore, we found that the combination of the HER2 inhibitor (CP-724714) and pan PI3K inhibitor (LY294002) is more potent than either inhibitor alone in terms of inhibition of cell proliferation and colony formation. Significantly, four cell signaling pathways were found in common for cells with HER2, mutant PIK3CA and cells with both genetic alterations through an Affymetric microarray analysis. Moreover, the cells with both genetic alterations acquired more significant replication stress as shown by enriched signaling pathways of cell cycle checkpoint control and DNA damage response signaling. Our study suggests co-occurrence of oncogenic HER2 and mutant PIK3CA cooperatively drives breast cancer progression. The cells with both genetic alterations obtain additional features of replication stress which could open new opportunity for cancer diagnostics and treatment.

CP-724714 is a potent, selective inhibitor of HER2/ErbB2 with IC50 of 10 nM, >640-fold selectivity against EGFR, InsR, IRG-1R, PDGFR, VEGFR2, Abl, Src, c-Met etc in cell-free assays. Phase 2.

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