Peptidomimetic Src/pretubulin inhibitor KX-01 alone and in combination with paclitaxel suppresses growth, metastasis in human ER/PR/HER2-negative tumor xenografts.
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.
1Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
Muralidharan
M
Anbalagan
Alaa
A
Ali
Ryan K
RK
Jones
Carolyn G
CG
Marsden
Mei
M
Sheng
Latonya
L
Carrier
Yahao
Y
Bu
David
D
Hangauer
Brian G
BG
Rowan
D000081:Acetamides / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib; D004357:Drug Synergism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009025:Morpholines; D009361:Neoplasm Invasiveness; D061206:Neoplasm Micrometastasis / Q000517:prevention & control; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D057786:Peptidomimetics / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D050257:Tubulin Modulators / Q000494:pharmacology / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000378:metabolism
D000081:Acetamides; D000970:Antineoplastic Agents; D000069439:Dasatinib; D047628:Estrogen Receptor alpha; D051417:Focal Adhesion Kinase 1; D009025:Morpholines; D017239:Paclitaxel; D057786:Peptidomimetics; D011725:Pyridines; D011743:Pyrimidines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone; D013844:Thiazoles; D050257:Tubulin Modulators; D019061:src-Family Kinases; C000713668:tirbanibulin; C508053:ERBB2 protein, human; C496050:PTK2 protein, human