Targeting MET and EGFR crosstalk signaling in triple-negative breast cancers

Abstract

There is a vital need for improved therapeutic strategies that are effective in both primary and metastatic triple-negative breast cancer (TNBC). Current treatment options for TNBC patients are restricted to chemotherapy; however tyrosine kinases are promising druggable targets due to their high expression in multiple TNBC subtypes. Since coexpression of receptor tyrosine kinases (RTKs) can promote signaling crosstalk and cell survival in the presence of kinase inhibitors, it is likely that multiple RTKs will need to be inhibited to enhance therapeutic benefit and prevent resistance. The MET and EGFR receptors are actionable targets due to their high expression in TNBC; however crosstalk between MET and EGFR has been implicated in therapeutic resistance to single agent use of MET or EGFR inhibitors in several cancer types. Therefore it is likely that dual inhibition of MET and EGFR is required to prevent crosstalk signaling and acquired resistance. In this study, we evaluated the heterogeneity of MET and EGFR expression and activation in primary and metastatic TNBC tumorgrafts and determined the efficacy of MET (MGCD265 or crizotinib) and/or EGFR (erlotinib) inhibition against TNBC progression. Here we demonstrate that combined MET and EGFR inhibition with either MGCD265 and erlotinib treatment or crizotinib and erlotinib treatment were highly effective at abrogating tumor growth and significantly decreased the variability in treatment response compared to monotherapy. These results advance our understanding of the RTK signaling architecture in TNBC and demonstrate that combined MET and EGFR inhibition may be a promising therapeutic strategy for TNBC patients.

Genomic Status ofMETPotentiates Sensitivity to MET and MEK Inhibition in NF1-Related Malignant Peripheral Nerve Sheath Tumors

“…Our results and other TKI studies suggest targeted inhibition of multiple kinase nodes may be required to minimize response variability and abrogate bypass mechanisms of resistance (38–40). Since RAS deregulation is a hallmark of NF1-related tumors, we also evaluated the efficacy of MEK inhibition in our models (21).…”

Therapeutic activity of DCC‐2036, a novel tyrosine kinase inhibitor, against triple‐negative breast cancer patient‐derived xenografts by targeting AXL/MET

“…As a novel third‐generation TKI, DCC‐2036 has a broader kinase inhibition profile than second‐generation TKIs, such as dasatinib, sorafenib and gefitinib. DCC‐2036 potently inhibits multitargets, including SRC, RAF, VEGFR2, AXL and MET, which are activated and/or highly expressed in multiple TNBC subtypes . Our study indicated that DCC‐2036 efficiently inhibits TNBC in vitro and in vivo .…”

“…DCC-2036 potently inhibits multitargets, including SRC, RAF, VEGFR2, AXL and MET, 20 which are activated and/or highly expressed in multiple TNBC subtypes. 12,[22][23][24] Our study indicated that DCC-2036 efficiently inhibits TNBC in vitro and in vivo. First, DCC-2036 showed more potent antiproliferative activity in TNBC cell lines (MDA-MB-231 and HS-578T) than most common clinically used drugs for breast cancer, including cisplatin, gemcitabine, lapatinib, tamoxifen, 5-FU and gefitinib.…”

FEN1 mediates miR‐200a methylation and promotes breast cancer cell growthviaMET and EGFR signaling

“…Constitutively activated tyrosine kinase receptors, such as MET and EGFR, have been identified as a main reason for cancer cell survival, including breast cancer (52)(53)(54)(55). Both MET and EGFR were predicted to be the target gene of miR-200a-5p using an online miR target gene prediction database.…”