Mobilization of a Unique Coregulatory Mechanism between Autophagy and Apoptosis for Breast Cancer Therapy
Abstract
Amplification of HER2 is seen in approximately 25%-30% of human breast cancer (BrCA) and is associated with a more malignant phenotype and a worse prognosis. Trastuzumab (Herceptin) is a recombinant humanized mAb directed against the extracellular domain of the signaling receptor HER2. Although it has been established that Herceptin is active against certain HER2-expressing BrCA, the response rate to Herceptin monotherapy is low, and the majority of the patients who achieve an initial response to such therapy acquire resistance within 1 year of treatment initiation. Lapatinib is a small molecule inhibitor that targets two members of the HER receptor family -- EGFR/HER1 and HER2. Unlike Herceptin, lapatinib enters the cells and binds to the intracellular domains of HER1/2, allowing for a complete blockage of the signaling cascade via these receptors. Although lapatinib induces a program of cell death mechanism -- apoptosis -- in certain HER2-overexpressing BrCA cells that are resistant to Herceptin, a significant proportion of the HER2-expressing BrCA cells remain resistant to treatments with Herceptin, lapatinib, or their combination. Our preliminary studies suggest that in HER2-expressing BrCA cells that do not succumb to lapatinib toxicity, the drug treatment gives rise to a cytoprotective mechanism -- autophagy -- that potentially mitigates the drug-mediated "stress," allowing the tumor cells to adapt and survive. Thus, independent of the primary resistance mechanism of BrCA to lapatinib, the autophagic adaptation following treatment supports the survival of the targeted tumor cells. Autophagy is a cellular degradation process that is involved in the elimination of damaged organelles and aggregated proteins. It is regulated by ATG genes that are stimulated by cellular stress to assemble double-membrane autophagic vesicles (termed "autophagosomes") around cytoplasmic constituents. Autophagosomes participate in the transport process of the sequestered cargo to lysosomes for degradation. Autophagy is frequently activated in tumor cells exposed to cytotoxic drugs, and it may confer therapy resistance by clearing damaged organelles and cellular stress by-products whose lysosomal degradation generates essential metabolites. Inhibition of autophagy has been demonstrated to enhance the effect of chemotherapy in multiple preclinical studies. Likewise, lapatinib induces protective autophagy in certain BrCA cells that do not succumb to its toxicity, and the inhibition of this adaptive response sensitizes more tumor cells to lapatinib. Our preliminary studies identified a surprising survival function within autophagy for caspase-9 (C9), an enzyme known to be involved in the apoptotic cell death cascade, the desired tumor cell response to chemotherapy. We also obtained evidence that the coupling of C9 to the autophagic cascade is mediated by a hitherto unknown complex between C9 and Atg7, an essential autophagic protein. Furthermore, the interaction of Atg7 with C9 represses the latter s apoptotic activity. This newly identified complex offers a novel opportunity for the manipulation of the balance between apoptotic death and cytoprotective autophagy. Indeed, if the interaction of C9 with Atg7 inhibits the apoptotic activity of C9 while linking it to the autophagic machinery, a scenario can be envisioned where inhibition of the Atg7/C9 complex formation (e.g., by chemicals or small peptidic molecules) would potentially enhance the apoptotic activity of C9 in lapatinib-resistant BrCA cells. We have already identified the interaction sites between Atg7 and C9 and generated molecular tools capable of disrupting this complex. The proposed preclinical studies will determine the significance of the novel complex that we identified as a potential molecular target for sensitization of HER2-expressing BrCA to a Food and Drug Administration-approved HER2 targeting drug. In sum, the newly identified Atg7/C9 complex bring
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510048
Entities
People
- Hannah Rabinowich
Organizations
- United States Army
- University of Pittsburgh