Thursday, May 2, 2024
5/2/2024
Cancer patients receiving most types of chemotherapy experience dysgeusia, i.e., distorted taste, which is associated with depression, malnutrition, morbid weight loss, and interruption of life-prolonging treatment. Cells within taste buds are continually and rapidly renewed, and this constant turnover makes taste prone to disruption by cancer therapies. However, the underlying and likely multiple mechanisms perturbed by cancer drugs that cause dysgeusia are not known. Here we focus on a small subset of six tyrosine kinase inhibitors (TKIs) used routinely to manage metastatic renal cell carcinoma (mRCC). These drugs target tumors by inhibiting VEGFR1-3 and PDGFR¿ receptor tyrosine kinases (RTKs). Paradoxically, these receptors are not expressed in taste epithelium, leaving open the question of how these drugs distort taste. It is well known that mRCC TKIs inhibit many off-target RTKs, including the Kit receptor. Via investigation of TKI target data and comparison with RTKs expressed in taste epithelium, we find that Kit is one of the few “taste” RTKs inhibited by all 6 drugs. We now have extensive pilot data that suggest inhibition of Kit may in fact underlie dysgeusia caused by these TKIs and specifically sweet taste is impacted. Preliminarily we show: (1) in mice, Kit is expressed primarily in sweet taste receptor cells (TRCs); (2) TKI treatment of lingual organoids derived from adult mouse taste stem cells leads to reduced expression of Tas1r2, a marker of sweet cells; (3) mice given the TKI cabozantinib have fewer Tas1r2+ sweet TRCs after 2 weeks; and (4) mice have blunted sweet taste function after 4 weeks of cabozantinib. In sum, our preliminary finding suggest the multifaceted hypothesis that: TKIs used to treat kidney cancer impede production of sweet taste cells, and disrupt sweet taste function by inhibiting Kit signaling. Aim 1. To investigate if TKIs used to treat mRCC inhibit sweet TRC differentiation and/or survival. We combine molecular genetic lineage tracing of sweet TRCs with drug treatment in mice (Aim 1A) and organoids (Aim 1B) to assess if sweet TRCs fail to survive TKI treatment or if treatment blocks production of new sweet TRCS. Aim 2. To test if cabozantinib, which cause dysgeusia in patients, alters sweet taste function in mice. Our pilot data suggest sweet taste is specifically impacted, but we cannot rule out effects on other taste modalities. We will use both behavioral assays (Aim 2A) and taste nerve recordings (Aim 2B) to determine if sweet taste is altered in cabozantinib-treated mice and/or if taste function is more broadly impacted. Aim 3. To determine if paracrine Kit signaling within taste buds is required for sweet TRC production. In Aim 3A, we will use western blotting of lingual organoids to assess if Kit signaling is inhibited by mRCC TKIs. Our pilot data reveal SCF, the ligand for the Kit receptor is expressed by glial-like cells and sour TRCs within taste buds. In Aim 3B, we will use conditional molecular genetics in mice to test if glial and sour TRCs signaling via SCF to Kit+ sweet TRCs is required for sweet TRC differentiation and/or survival, and sweet taste function.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
