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-MB-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-MB-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-MB-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-MB-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.
Stickler et al. (Wed,) studied this question.