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JAAD Case Reports Oct 2023
PubMed: 37817888
DOI: 10.1016/j.jdcr.2023.07.005 -
Molecular Cancer Therapeutics Sep 2012Src kinase is elevated in breast tumors that are ER/PR negative and do not overexpress HER2, but clinical trials with Src inhibitors have shown little activity. The...
Src kinase is elevated in breast tumors that are ER/PR negative and do not overexpress HER2, but clinical trials with Src inhibitors have shown little activity. The present study evaluated preclinical efficacy of a novel peptidomimetic compound, KX-01 (KX2-391), that exhibits dual action as an Src and pretubulin inhibitor. KX-01 was evaluated as a single-agent and in combination with paclitaxel in MDA-MB-231, MDA-MB-157, and MDA-MB-468 human ER/PR/HER2-negative breast cancer cells. Treatments were evaluated by growth/apoptosis, isobologram analysis, migration/invasion assays, tumor xenograft volume, metastasis, and measurement of Src, focal adhesion kinase (FAK), microtubules, Ki67, and microvessel density. KX-01 inhibited cell growth in vitro and in combination with paclitaxel resulted in synergistic growth inhibition. KX-01 resulted in a dose-dependent inhibition of MDA-MB-231 and MDA-MB-157 tumor xenografts (1 and 5 mg/kg, twice daily). KX-01 inhibited activity of Src and downstream mediator FAK in tumors that was coincident with reduced proliferation and angiogenesis and increased apoptosis. KX01 also resulted in microtubule disruption in tumors. Combination of KX-01 with paclitaxel resulted in significant regression of MDA-MB-231 tumors and reduced metastasis to mouse lung and liver. KX-01 is a potently active Src/pretubulin inhibitor that inhibits breast tumor growth and metastasis. As ER/PR/HER2-negative patients are candidates for paclitaxel therapy, combination with KX-01 may potentiate antitumor efficacy in management of this aggressive breast cancer subtype.
Topics: Acetamides; Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Dasatinib; Drug Synergism; Estrogen Receptor alpha; Female; Focal Adhesion Kinase 1; Humans; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Morpholines; Neoplasm Invasiveness; Neoplasm Micrometastasis; Neovascularization, Pathologic; Paclitaxel; Peptidomimetics; Pyridines; Pyrimidines; Receptor, ErbB-2; Receptors, Progesterone; Thiazoles; Tubulin Modulators; Tumor Burden; Xenograft Model Antitumor Assays; src-Family Kinases
PubMed: 22784709
DOI: 10.1158/1535-7163.MCT-12-0146 -
Oncotarget Aug 2016Application of tumor genome sequencing has identified numerous loss-of-function alterations in cancer cells. While these alterations are difficult to target using direct...
Application of tumor genome sequencing has identified numerous loss-of-function alterations in cancer cells. While these alterations are difficult to target using direct interventions, they may be attacked with the help of the synthetic lethality (SL) approach. In this approach, inhibition of one gene causes lethality only when another gene is also completely or partially inactivated. The EPHB6 receptor tyrosine kinase has been shown to have anti-malignant properties and to be downregulated in multiple cancers, which makes it a very attractive target for SL applications. In our work, we used a genome-wide SL screen combined with expression and interaction network analyses, and identified the SRC kinase as a SL partner of EPHB6 in triple-negative breast cancer (TNBC) cells. Our experiments also reveal that this SL interaction can be targeted by small molecule SRC inhibitors, SU6656 and KX2-391, and can be used to improve elimination of human TNBC tumors in a xenograft model. Our observations are of potential practical importance, since TNBC is an aggressive heterogeneous malignancy with a very high rate of patient mortality due to the lack of targeted therapies, and our work indicates that FDA-approved SRC inhibitors may potentially be used in a personalized manner for treating patients with EPHB6-deficient TNBC. Our findings are also of a general interest, as EPHB6 is downregulated in multiple malignancies and our data serve as a proof of principle that EPHB6 deficiency may be targeted by small molecule inhibitors in the SL approach.
Topics: Acetamides; Animals; Breast Neoplasms; Cell Death; Cell Line, Tumor; Cell Membrane; Female; Fluorescent Dyes; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genome-Wide Association Study; Humans; Immunohistochemistry; Indoles; Mice; Mice, Inbred NOD; Mice, SCID; Morpholines; Pyridines; RNA, Small Interfering; Receptors, Eph Family; Sulfonamides; Synthetic Lethal Mutations; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays; src-Family Kinases
PubMed: 27418135
DOI: 10.18632/oncotarget.10569 -
Cancer Chemotherapy and Pharmacology Apr 2013KX2-391 is an oral non-ATP-competitive inhibitor of Src kinase and tubulin polymerization. In phase 1 trials, prostate-specific antigen (PSA) declines were seen in...
PURPOSE
KX2-391 is an oral non-ATP-competitive inhibitor of Src kinase and tubulin polymerization. In phase 1 trials, prostate-specific antigen (PSA) declines were seen in patients with advanced prostate cancer. We conducted a single-arm phase 2 study evaluating KX2-391 in men with chemotherapy-naïve bone-metastatic castration-resistant prostate cancer (CRPC).
METHODS
We treated 31 patients with oral KX2-391 (40 mg twice-daily) until disease progression or unacceptable toxicity. The primary endpoint was 24-week progression-free survival (PFS); a 50 % success rate was pre-defined as clinically significant. Secondary endpoints included PSA progression-free survival (PPFS) and PSA response rates. Exploratory outcomes included pharmacokinetic studies, circulating tumor cell (CTC) enumeration, and analysis of markers of bone resorption [urinary N-telopeptide (uNTx); C-telopeptide (CTx)] and formation [bone alkaline phosphatase (BAP); osteocalcin].
RESULTS
The trial closed early after accrual of 31 patients, due to a pre-specified futility rule. PFS at 24 weeks was 8 %, and median PFS was 18.6 weeks. The PSA response rate (≥ 30 % decline) was 10 %, and median PPFS was 5.0 weeks. Additionally, 18 % of men with unfavorable (≥ 5) CTCs at baseline converted to favorable (<5) CTCs with treatment. The proportion of men with declines in bone turnover markers was 32 % for uNTx, 21 % for CTx, 10 % for BAP, and 25 % for osteocalcin. In pharmacokinetic studies, median C max was 61 (range 16-129) ng/mL, and median AUC was 156 (35-348) ng h/mL. Common toxicities included hepatic derangements, myelosuppression, fatigue, nausea, and constipation.
CONCLUSION
KX2-391 dosed at 40 mg twice-daily lacks antitumor activity in men with CRPC, but has modest effects on bone turnover markers. Because a C max of ≥142 ng/mL is required for tubulin polymerization inhibition (defined from preclinical studies), higher once-daily dosing will be used in future trials.
Topics: Acetamides; Administration, Oral; Aged; Aged, 80 and over; Bone Neoplasms; Bone and Bones; Humans; Male; Middle Aged; Morpholines; Neoplastic Cells, Circulating; Orchiectomy; Prostatic Neoplasms; Pyridines; Tubulin Modulators; src-Family Kinases
PubMed: 23314737
DOI: 10.1007/s00280-013-2079-z