Multipronged Cotargeting of ALK/ROS1 and Compensatory Focal Adhesion Kinases in Lung Cancer as a Preemptive Strike to Prevent Development of Drug Resistance
Abstract
Area(s) of Emphasis: 1. Identify innovative strategies for the treatment of lung cancer; 2. Understand mechanisms of resistance to treatment (primary and secondary). Lung cancer is the most common cancer type across men and women combined and the number 1 cause of cancer- related death in the U.S. and worldwide. Whereas targeted therapy provides significant clinical benefit to patients with non-small cell lung cancers (NSCLC) that are driven by oncogenes, such as ALK or ROS1 gene fusions, drug resistance almost inevitably develops, which leads to disease progression, patient relapse and, ultimately, death. Multiple different resistance mechanisms have been described and, although drugs and experimental therapies can address some of these, for many mechanisms there are currently no effective therapies available and it is through these mechanisms that tumors will eventually escape therapy. This is of particular relevance for ALK- and ROS1- positive NSCLC as patients with these tumors are considerably younger than most other cancer patients, often in their 30s or 40s like many active military Service Members and their spouses, and therapeutic strategies are desperately needed that prolong survival not just by a few years, as is currently the case, but by decades. Targeting the oncogene drivers is an absolute necessity for these NSCLCs, but an alternative to this reactionary whack-a-mole endeavor, which we will lose eventually, is the development of upfront combination therapies that deliver a preemptive strike and thus prevent or significantly delay the emergence of drug resistance, which is the objective of this proposal. Key to achieving this is targeting of drug-tolerant persister cells, which are initially drug-sensitive cancer cells that have been shown to enter a semi-dormant (persister) state upon drug therapy and survive over a long period of time, during which they then can acquire genetic resistance mechanisms. Importantly, only very few cells initially exist in the persister state. Rather, the vast majority of them enter it only upon challenge by drug treatment, making it more advantageous to target the switch to, rather than persisterness itself, which is a novel concept. Little is known about the mechanisms used by cancer cells to engage this persister switch, which allows them to rapidly transition from a proliferating to a persister state. We and others have observed rapid changes in the flow of oncogenic signals (compensatory signaling) in various cancer cells in response to targeted drugs, which supports the survival of some otherwise sensitive cancer cells upon drug treatment and thus prevents full eradication of tumor cells. Our preliminary data suggest that the focal adhesion kinases PYK2 and SRC play a critical role in directing the network-wide compensatory signaling in ALK- and ROS1-positive NSCLC cells thereby leading to enhanced cancer cell survival and an increased number of persister cells. We furthermore observed that among clinically approved drugs some by chance also target PYK2 and thereby strongly synergize with SRC inhibitors. We therefore hypothesize that upfront multipronged co-targeting of ALK/ROS1 fusion oncogenes together with PYK2-SRC- mediated compensatory survival signaling more effectively induces NSCLC cell death and reduces persister pools. We propose the following Specific Aims: 1. To determine PYK2 and SRC mediated network-wide signaling adaptations to targeted drugs and their relevance for lung cancer cell survival. We will apply state-of-the-art functional proteomics technologies that allow for identification of rapid compensatory signaling mechanisms. Integrated network-wide analysis will identify drug targets that impact the compensatory signaling response. Validation of key targets and network proteins will be performed using a variety of genetic, pharmacological and biochemical methods in cancer cells and archived patient tumor tissues. This i
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210607
Entities
People
- Uwe Rix
Organizations
- H. Lee Moffitt Cancer Center & Research Institute
- United States Army