Cell line-specific network models of er breast cancer identify potential pi3kainhibitor resistance mechanisms and drug combinations

Jorge Gómez Tejeda Zañudo, Pingping Mao, Clara Alcon, Kailey Kowalski, Gabriela N. Johnson, Guotai Xu, Jose Baselga, Maurizio Scaltriti, Anthony Letai, Joan Montero, Réka Albert, Nikhil Wagle

Research output: Contribution to journalArticlepeer-review

Abstract

Durable control of invasive solid tumors necessitates identifying therapeutic resistance mechanisms and effective drug combinations. In this work, we used a network-based mathematical model to identify sensitivity regulators and drug combinations for the PI3Ka inhibitor alpelisib in estrogen receptor positive (ER) PIK3CAmutant breast cancer. The model-predicted efficacious combination of alpelisib and BH3 mimetics, for example, MCL1 inhibitors, was experimentally validated in ER breast cancer cell lines. Consistent with the model, FOXO3 downregulation reduced sensitivity to alpelisib, revealing a novel potential resistance mechanism. Cell line-specific sensitivity to combinations of alpelisib and BH3 mimetics depended on which BCL2 family members were highly expressed. On the basis of these results, newly developed cell line-specific network models were able to recapitulate the observed differential response to alpelisib and BH3 mimetics. This approach illustrates how network-based mathematical models can contribute to overcoming the challenge of cancer drug resistance.

Original languageEnglish (US)
Pages (from-to)4603-4617
Number of pages15
JournalCancer Research
Volume81
Issue number17
DOIs
StatePublished - Sep 1 2021

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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