Timeframe: 2025 – 2027
Goal: Model development
Principal Investigator: Nabeel Bardeesy, PhD
Study overview: Typically, cancers requires activation of a “driver” of uncontrolled growth, such as the DNAJB1-PRKACA (DP) fusion in FLC, coupled with the loss of a “tumor suppressor” function. Tumor suppressors act as “brakes” on cancers, by causing cells that have gone out of control to undergo programmed suicide.
Surprisingly, studies of FLC have not revealed consistent losses or inactivation of known tumor suppressor genes. However, in previous work funded by FCF, Dr. Nabeel Bardeesy discovered why the production of DP apparently suffices to cause FLC. His lab recently showed that the DP protein causes sustained inhibition of a family of “salt inducible protein kinases” (SIKs)*. The SIK proteins are known tumor suppressors. The Bardeesy team, therefore, concluded that, rather than depending on independent genetic events to inactivate a tumor suppressor, the DP protein itself simply turns OFF the activity of the SIK protein(s). This finding reveals a “core mechanism” by which DP causes FLC.
In that work, Dr. Bardeesy provided a mechanistic model for how inactivation of SIK function by DP contributes to FLC formation. Like all protein kinases, the SIKs work by attaching a small chemical “tag” (a phosphate group) onto specific sites on various target proteins to regulate their activity. The addition or subtraction of the tag often toggles a protein between ON (active) and OFF (inactive) states. The presence or absence of the tag also may change the stability of the protein and/or alter its location in the cell. When the SIKs are ON, they suppress (turn OFF) the expression of key gene programs that drive cells to proliferate and to produce essential metabolites for growth. Conversely, when DP switches the SIKs OFF, an important consequence is the switching ON of the genetic programs which enable cells to proliferate.
The proposal seeks to leverage the knowledge that DP works directly through inactivating SIKs to devise new treatments for FLC. The immediate proximity of SIK inactivation to the fundamental driver of FLC could make it especially attractive for targeted cancer therapy. Through this study, Dr. Bardeesy proposes to explore the feasibility of two classes of therapies:
- Drugs that inhibit proteins which are responsible for cancer-specific gene expression, and which are made in FLC cells as a direct result of switching OFF SIK. Two important examples of such proteins are named P300 and CRTC. These are “transcription coactivators” which cooperate to promote the expression of genes essential for the survival and malignant growth of FLC cancers.
- Drugs that activate SIK kinase(s) in a manner that overcomes the block caused by DP. This should restore SIK’s tumor suppressor activity, thereby preventing the proliferation of FLC cells, and potentially triggering “programmed cell death,” a crucial feature of many successful cancer therapies.
If successful, this project could:
- Confirm the working model that an important element of cancer causation in FLC is the inactivation of the SIK family kinases by DP, which turns OFF their tumor suppressor function.
- Determine whether drugs being developed as activators of SIK kinases can kill FLC cells and whether they deserve further attention as potential FLC therapeutics.
- Provide mechanistic understanding of how inhibition of SIK by DP reprograms gene expression in FLC cancer cells.
* Gritti, et al., Cancer Discovery, 2025