Lineage specific MYC-signaling
In the past decade the rapid characterization of the cancer genome paralleled by the development of highly active targeted drugs revolutionized cancer medicine by enabling the transition from empirical testing of cytotoxic agents towards the tailored targeting of oncogenically activated proteins that drive tumor development. Inspired by this development we and others have identified novel genetic lesions (e.g. amplified FGFR1) that may render tumors responsiveness to targeted drugs. These genetic alterations show lineage-restricted (lineage=unique tissue of origin, e.g. lung, breast, etc.) patterns, indicating that lineage-specific programs, harbored by tumor precursor cells might condition genetic changes in cancer.
One of the most common genetic alterations found in human cancer are amplifications of Myc gene family members (c-MYC, MYCL1, MYCN) that result in deregulated Myc signaling. Interestingly, each individual tumor has a preference for the amplification of a specific member of the Myc family and this typically correlates with the lineage: c-MYC in non-small cell lung cancer, MYCL1 and c-MYC primarily in small cell lung cancer and MYCN is typically found in neuroblastoma patients and is linked with poor outcome. This lineage specificity has broad implications for the transcriptional and posttranslational regulation of the cellular networks and therefore will affect the response to targeted cancer drugs. We were able to show that c-MYC driven small-cell lung tumors are dependent on the activity of Aurora kinase B (Aurk B) that can be effectively inhibited by Aurk B inhibitors. Other studies show that in MYCN-amplified neuroblastoma cells Aurora kinase A is an important mediator of protein stability of MYCN and therefore may serve as a potential target for the treatment of these tumors. However, it remains unclear how much the lineage dictates the dependency on the expression of the individual Myc family members and what mechanistically determines AurK inhibitor activity in these tumors.
Our project represents an integrated genomics, proteomics and chemical biology approach to characterize these lineage-specific programs that modulate Myc signaling and efficacy of targeted AurK inhibition by addressing three major aims:
- Aim 1. Define lineage-specific Myc-dependency in cancer.
- Aim 2. Characterize lineage-specific AurK signaling networks in Myc-dependent cells.
- Aim 3. Functionally link lineage-specific Myc-dependency to AurK inhibitor efficacy.
Our data will provide important insights into the biology of deregulated Myc signaling and may guide the rational design of novel therapeutics for subgroups of cancer patients.