title: Biomarker-guided sequential targeted therapies to overcome therapy resistance in rapidly evolving highly aggressive mammary tumors.
abstract: Combinatorial targeted therapies are more effective in treating cancer by blocking by-pass mechanisms or inducing synthetic lethality. However, their clinical application is hampered by resistance and toxicity. To meet this important challenge, we developed and tested a novel concept of biomarker-guided sequential applications of various targeted therapies using ErbB2-overexpressing/PTEN-low, highly aggressive breast cancer as our model. Strikingly, sustained activation of ErbB2 and downstream pathways drives trastuzumab resistance in both PTEN-low/trastuzumab-resistant breast cancers from patients and mammary tumors with intratumoral heterogeneity from genetically-engineered mice. Although lapatinib initially inhibited trastuzumab-resistant mouse tumors, tumors by-passed the inhibition by activating the PI3K/mTOR signaling network as shown by the quantitative protein arrays. Interestingly, activation of the mTOR pathway was also observed in neoadjuvant lapatinib-treated patients manifesting lapatinib resistance. Trastuzumab + lapatinib resistance was effectively overcome by sequential application of a PI3K/mTOR dual kinase inhibitor (BEZ235) with no significant toxicity. However, our p-RTK array analysis demonstrated that BEZ235 treatment led to increased ErbB2 expression and phosphorylation in genetically-engineered mouse tumors and in 3-D, but not 2-D, culture, leading to BEZ235 resistance. Mechanistically, we identified ErbB2 protein stabilization and activation as a novel mechanism of BEZ235 resistance, which was reversed by subsequent treatment with lapatinib + BEZ235 combination. Remarkably, this sequential application of targeted therapies guided by biomarker changes in the tumors rapidly evolving resistance doubled the life-span of mice bearing exceedingly aggressive tumors. This fundamentally novel approach of using targeted therapies in a sequential order can effectively target and reprogram the signaling networks in cancers evolving resistance during treatment.
authors.affiliation: 1] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA [2] Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey 06800.
authors.forename: Ozgur
authors.initials: O
authors.lastname: Sahin
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Qingfei
authors.initials: Q
authors.lastname: Wang
authors.affiliation: 1] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA [2] Cancer Biology Program, Graduate School of Biomedical Sciences-Houston, TX 77030, USA.
authors.forename: Samuel W
authors.initials: SW
authors.lastname: Brady
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Ellis
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Wang
authors.affiliation: 1] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA [2] Cancer Biology Program, Graduate School of Biomedical Sciences-Houston, TX 77030, USA.
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Qingling
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: 1] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA [2] Cancer Biology Program, Graduate School of Biomedical Sciences-Houston, TX 77030, USA.
authors.forename: Preety
authors.initials: P
authors.lastname: Priya
authors.affiliation: The Methodist Cancer Center, Houston, TX 77030, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhu
authors.affiliation: The Methodist Cancer Center, Houston, TX 77030, USA.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Wong
authors.affiliation: The Methodist Cancer Center, Houston, TX 77030, USA.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Landis
authors.affiliation: Goodman Cancer Center, McGill University, Montreal, Quebec, H3A 1A3, Canada.
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
authors.affiliation: Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Esteva
authors.affiliation: The Methodist Cancer Center, Houston, TX 77030, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang
authors.affiliation: 1] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA [2] Cancer Biology Program, Graduate School of Biomedical Sciences-Houston, TX 77030, USA.
authors.forename: Dihua
authors.initials: D
authors.lastname: Yu
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001940:Breast / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D000077341:Lapatinib; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy / Q000379:methods*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007093:Imidazoles; D000077341:Lapatinib; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D000068878:Trastuzumab; C531198:dactolisib