Screening of kinase inhibitors in the triple negative KRAS G13D-mutated MDA-MB-231 breast cancer cell line
C‑Abl and HER2/ERBB2 inhibitors, such as Bosutinib, Dasatinib and Neratinib, enhance the antiproliferative and anti‑migration efficacy of KRAS inhibitors in KRAS G13D‑mutated triple‑negative breast cancer cells, offering potential combination strategies to overcome resistance.
Triple negative breast cancer (TNBC) is more chemoresistant and has a poorer prognosis than other breast cancer types. A subset of TNBCs carries KRAS mutations or amplifications. MDA‑MBC‑231 cells, which have a KRAS G13D mutation and express HER2‑103, were previously shown to be sensitive to the KRAS G12D inhibitor MRTX1133 and ERBB2‑targeting drugs. A kinase inhibitor library of 157 compounds was screened against MDA‑MBC‑231 cells. Effective compounds and ERBB2‑directed drugs were tested for synergistic antiproliferative effects in combination with two KRAS inhibitors and for their impact on cell migration. The BCR‑ABL/SRC inhibitors Bosutinib and Dasatinib showed strong activity, while the SRC inhibitor Saracatinib was less effective. MDA‑MBC‑231 lacks BCR‑ABL but expresses c‑Abl, as shown by Western blot and comparison with K562 cells. The tricomplex RAS(ON) inhibitor RMC‑7977 was more effective than MRTX1133. Combinations of KRAS inhibitors with Bosutinib, Dasatinib, Saracatinib (to a lesser extent), and ERBB2 inhibitors Neratinib and Mobocertinib enhanced antiproliferative effects. These findings highlight c‑Abl as a relevant target in MDA‑MBC‑231 TNBC cells. C‑Abl and ERBB2 inhibitors can enhance the efficacy of KRAS‑targeted therapies, offering potential combination strategies to overcome resistance in KRAS‑positive TNBC.
These findings highlight c‑Abl as a relevant target in MDA‑MBC‑231 TNBC cells. C‑Abl and ERBB2 inhibitors can enhance the efficacy of KRAS‑targeted therapies, offering potential combination strategies to overcome resistance in KRAS‑positive TNBC.
Bizonyítékszint: Klinikai vizsgálat. Formális klinikai vizsgálati eredmény.
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