Mechanisms of Resistance to PI3K inhibitors

PI3K inhibitors are used in breast, lung and several other types of cancers. Combination therapies can be elucidated from the mechanisms that limit the PI3K inhibitor sensitivity of cancer cells. To tackle this issue, we are using different approaches: transposone library screening, ORF kinase overexpression screening, and in vivo acquired resistance models. Furthermore, it is critical that we analyze samples from patients undergoing treatment with PI3K inhibitors and compare them to laboratory findings. To obtain these samples — or biopsies — we collaborate with radiologists and oncologists and study acute changes in protein expression and phosphorylation or genomic aberrations upon and/or following therapy.

Early Molecular Responses to Treatment and Efficacy of Novel Therapeutic Combinations

Therapeutic inhibition of an oncoprotein silences the oncogene-dependent signaling, and activates upstream receptors and parallel compensatory pathways (silent in absence of oncogene inhibition) that limit the efficacy of the targeted therapy. Such adaptive resistance is well illustrated when rapamycin or rapalogs inhibit mTORC1, turning on a negative feedback loop via the insulin-like growth factor receptor, which finally activates Akt. In the same fashion, inhibition of PI3K/Akt in HER2-positive breast cancer cells leads to a compensatory activation of the ERK pathway, mediated by induction of HER3 expression leading to hyperphosphorylation of the HER receptors. Along with others, we have demonstrated that “synthetic lethality-like” effects can be achieved by disrupting theses adaptive pathways using combined targeted approaches.

We are testing the activity of PI3K inhibitors with MEK inhibitors, mTOR inhibitors, and agents that target upstream receptor tyrosine kinases.

Resistance to Anti-HER2 Agents

Despite the unquestionable success of trastuzumab and other anti-HER2 agents in the treatment of HER2-positive breast cancer, resistance to these therapies is still a major problem in the metastatic setting.

We are currently working on different projects aimed to:

  1. Uncover novel candidate genes responsible for resistance to trastuzumab, lapatinib, or the combination of both through in vitro and in vivo models
  2. Analyze tissue samples from HER2 positive breast cancer patients (who received anti-HER2 therapy) to uncover novel (or validate proposed) mechanisms of resistance to anti-HER2 agents. The final purpose of these studies is twofold: to identify those patients who are less likely to respond to a given anti-HER2 therapy and to design ad hoc clinical trials testing new combinatorial therapeutic strategies for these resistant patients.