Figure 1.

Metabolic adaptations drive acquired drug resistance in breast cancer cells. (Left) In drug-sensitive cells, cell growth and proliferation are dependent on receptor tyrosine kinase (RTK) signaling. RTK signaling induces Ras and PI3K pathway activity that in turn modulates (arrows) multiple aspects of cellular metabolism that are required for cell growth and proliferation. Upon treatment of Lapatinib, RTK signaling is disrupted and activity of its downstream effectors is abrogated. Consequently, Ras and PI3K signaling is inhibited and oncogene-dependent metabolic rewiring is prevented. As a result, cancer cell death is observed. (Right) In drug-resistant cells, the Ras and PI3K pathways remain inhibited by Lapatinib treatment. However, disruption of these signaling pathways is insufficient to alter cellular metabolism and stress responses. As a result, cells remain viable and continue to proliferate in the absence of RTK signaling and Ras and PI3K pathway activity.