Ras-Induced Resistance to Lapatinib is Overcome by MEK Inhibition

Abstract

Lapatinib, a dual HER2 and EGFR tyrosine kinase inhibitor is highly active in HER2+ breast cancer. However, its efficacy is limited by either primary or acquired resistance. Although mutations in ras genes are rarely found in breast cancer, H-ras overexpression is frequently observed. Moreover, genetic alterations that do not directly involve ras such as Brk amplification, ultimately result in increased ras signaling. Using SKBR3 cells, a HER2+ breast cancer cell line that is naturally devoid of mutations in PI3KCA, PTEN, BRAF, and ras we show that both H-ras overexpression and expression of an oncogenic ras allele (ras V12) reduce susceptibility to lapatinib in analogy to what observed with activating PI3KCA mutations and with a constitutively active form of Akt. Importantly, we found that resistance to lapatinib due to ras overexpression or to ras V12 is overcome by MEK inhibition with U0126, suggesting a key role for the MEK-Erk pathway in ras-induced resistance. Similar results were obtained in BT474 cells, another HER+ breast cancer cell line. Therefore, our data indicate that overexpressed/mutated ras may act as a biological modifier of the response to lapatinib. Combining MEK inhibitors with lapatinib may help overcome this form of resistance and increase the efficacy of lapatinib in these tumors.

Inhibition of MCL-1 in breast cancer cells promotes cell death in vitro and in vivo

“…SKBR3 and BT474 cells overexpress ERBB2 and BT474 and MCF7 cells express a mutant active PI3K protein, and as a result of these genetic alterations all of these cells have been argued to be more dependent on AKT signaling for growth and cell survival than the MEK-ERK pathway. 40 In contrast to other systems where we have observed BAX/BAK dependent tumor cell killing that was associated with JNK and/or p38 MAPK signaling, CDK inhibitor + lapatinib toxicity was apparently not dependent on the JNK or p38 MAPK pathways to promote the activation of the toxic BH3 domain proteins. 30 Knock down of MCL-1 and BCL-X L enhanced lapatinib toxicity in breast cancer cells; this is similar to our prior observations in colon cancer cells.…”

Dynamic Simulations of Pathways Downstream of ERBB-Family, Including Mutations and Treatments: Concordance with Experimental Results

“…The highly correlative results obtained with our BT474 BC line were not selected from among a large set of experimental results and extracted a posteriori in a sort of retrofitting game. As a matter of fact, this is just one of only two experimental sets we generated in cell culture to test our simulations; upon repetition with the SKBR3 BC line, very similar results were obtained (data not reported and [75]). Simulations were performed at the sub-physiological concentration of 10 -3 nM to reproduce the EGF free medium conditions used with the cells.…”

MEK1/2 Inhibitors AS703026 and AZD6244 May Be Potential Therapies for KRAS Mutated Colorectal Cancer That Is Resistant to EGFR Monoclonal Antibody Therapy

“…The usage of these cell lines eliminates the possibility of partial effect by wild-type K-Ras in K-ras mutated cancer cells, when compared with the several previous trials related with therapeutic potential of MEK inhibitors on various cancer cells (43)(44)(45)(46). The data indicate clear resistance to EGFR mAb in the K-ras mutated cell line D-MUT, an advantage over most colorectal cancer cells that have heterozygous K-ras mutations.…”