Effective targeted therapies for cancer treatment rely on the identification of key molecular drivers responsible for tumour progression and patient stratification. However, acquisition of secondary mutations and clonal expansion of intrinsic resistant clones represent a challenge for the establishment of durable therapies. Constitutive activation of the PI3K-AKT-mTOR signal transduction pathway is frequently associated with breast cancer, and activating mutations in the upstream kinase PI3-K have been identified in almost 40% of ER+ breast cancer, making it an attractive target for cancer therapy.
The phosphatidylinositol 3-kinase (PI3-K) functions by phosphorylating the lipid substrate phosphatidylinositol (4,5)-bisphosphate (PIP2) to generate phosphatidylinositol (3,4,5)-trisphosphate (PIP3), which in turns activates the kinase AKT to promote cell growth and proliferation. PTEN is the tumour suppressor that dephosphorylates PIP3 and therefore opposes AKT activation. Recently, loss of PTEN was found to cause resistance to the PI3-K inhibitor Alpelisib (BYL719) in patients with PIK3CA-mutant breast cancers, suggesting that reactivation of the AKT signal through PTEN loss may be a causal event promoting cancer progression and resistance to PI3K-based therapies.
To investigate mechanisms of resistance to PI3-K inhibitors for breast cancer treatment, we have used the PI3K-mutant breast cancer cell line T47D and generated independent pools of cells resistant to two PI3K inhibitors: the p110a- isoform-specific PI3K inhibitor BYL719, and the pan-PI3K inhibitor BKM120. Through targeted studies and unbiased phospho-proteomics we have found that resistance to these inhibitors is not simply driven by reactivation of the proto-oncogene AKT but rather by the concerted activation of parallel pathways converging on key molecular nodes sustaining cell growth and proliferation in an AKT-independent manner.
Collectively, our studies provide new insights for the development of better and more personalised therapies for the treatments of breast cancer refractory to PI3K-based therapies.