Wednesday, April 2, 2025
4/2/2025
The kinase inhibited RTK forms a scaffold to drive therapeutic resistance in cancer - Targeted therapy of cancer generally involves inhibition of a specific oncogenic pathway that plays a key role as an oncogenic driver in the pathogenesis or maintenance of cancer. Targeted therapy has been most successful in the presence of activating mutations in receptor tyrosine kinase (RTK) pathways that result in accentuated signaling. However, secondary resistance to RTK inhibition is a major therapeutic hurdle. The emergence of secondary resistance implies the persistence of subsets of cancer cells that are not eliminated during the initial treatment. The mechanisms of secondary resistance have been investigated intensively. Both mutational and non-mutational mechanisms of resistance have been describe For example, major mutational mechanisms of resistance to EGFR inhibition in NSCLC include secondary EGFR mutations such as the T790M mutation, and amplification of other RTKs such as MET. These genetic changes are detected months after exposure to tyrosine kinase inhibitors (TKIs). In addition, inhibition of RTK signaling pathways in cancer cells leads to a rapid reprogramming of signaling pathways as the cancer cell tries to restore homeostasis. This adaptive response may protect cells from a loss of RTK signals and play an important role in mediating therapeutic resistance. Our preliminary data indicate that while tyrosine kinase inhibition blocks the kinase activity of RTKs, the RTK does not shut down. Exposure to TKIs triggers a rapid SUMOylation of the RTK and changes its function to an adaptor protein that continues to signal. In this proposal, we focus on mechanisms of resistance to TKIs with a focus on osimertinib treatment in EGFR mutant non-small cell lung cancer (NSCLC) and other activated RTKs to examine the mechanisms and biological significance of RTK SUMOylation in response to TKIs. Preliminary data indicate that osimertinib induces a rapid and biologically SUMOylation of mutant EGFR. EGFR SUMOylation changes its function from a RTK to an adaptor protein. We also detect a rapid SUMOylation of other RTKs following kinase inhibition. RTK SUMOylation constitutes a platform to generate two major facets of the adaptive response, i. e. TNF-NF-B activation and bypass RTK signaling. Both EGFR SUMOylation and activation can be detected in osimertinib treated tumors. In Specific Aim 1 we determine the mechanisms of RTK SUMOylation in response to TKI treatment. Preliminary data indicate that SUMOylation of the EGFR at K37 is required for both TNF-NF-B activation and bypass RTK signaling in response to osimertinib and leads to osimertinib resistance. We will also examine additional RTKs in this aim. In Specific Aim 2, we determine the mechanisms of NF-B and bypass RTK activation in response to tyrosine kinase inhibition. In Specific Aim 3, we determine the biological significance of TKI-induced RTK SUMOylation and its impact on secondary resistance with a particular focus on EGFR mutant NSCLC EGFR in multiple mouse models of NSCLC.
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