Abstract 158: A combination therapy of atypical protein kinase C inhibitors and phosphatidylinositol-3-kinase inhibitor reduces resistance & invasiveness in renal cell carcinoma (RCC)
Authors: Khalid Khandker Mohammad , Ratnayake Wishrawana S. , Apostolatos Christopher A. , Lajmi Luke , Breedy Sloan , Oishee Nuzhat N. , Acevedo-Duncan Mildred 
Published: June 2022

Renal Cell Carcinoma (RCC) is the most common type of kidney cancer (85%) of which 75% of the cases involve conventional clear cell RCC (ccRCC). Choice of treatments recommended for clear cell carcinoma and non-clear cell carcinoma are partial nephrectomy (Stage I), radical nephrectomy (Stage II and III) and chemotherapy (stage IV). Phosphatidylinositol-3- kinase (PI3K) inhibitors can be a viable candidate in the chemotherapy of ccRCC as the PI3K/PDK1 pathway is frequently activated in RCC. Hence, PI3K inhibitors like Alpelisib (BYL 719) can be a choice of treatment. In addition, aPKCs, PKC ί/λ and PKC ζ are overexpressed in most cancer cells and play a central role in tumor progression and metastasis of different type of cancers. Treatment of ccRCC metastatic clear cells with a combination of aPKC inhibitor [8-hydroxynaphthalene-1, 3, 6-trisulfonic acid] ζ-stat, or ICA-1 and BYL 719 inhibits PKC ί/λ and PKC ζ with the downstream inhibition of c-Myc (a major protein controlling cell survival and cell cycle progression in RCC). Inhibition of the aPKCs (PKC ί/λ and PKC ζ) also reduces the activation of other important proteins, for example, Mitogen-Activated Protein Kinase Kinase (MEK) and extracellular signal regulated kinase (ERK1/2). It is observed that treatment with ζ-stat, or ICA-1 disrupts the aPKC-AKT1 association which in turns reduces the activation of AKT1 through phosphorylation. ζ-stat, or ICA-1 treatment also disrupts association between aPKC and c-Myc. Inhibition of aPKCs and other downstream effector proteins by combination therapy is more pronounced compared to the single therapy. These effects contribute to reduced cell growth, cell survival and eventually induction of apoptosis. Boyden Chamber assay also suggested that there is decreased invasiveness of the cells when treated with the combination treatment. This can be due to the inactivation of both ERK1/2 and AKT by the combination treatment. In addition, efflux proteins, (p-glycoprotein (P-gp) and ATP-binding cassette sub-family G member 2 (ABCG2), responsible for developing cell resistance, had reduced expression

in the cells when treated with ζ-stat as a single therapy along with the combination of Alpelisib and ζ-stat. Hence, combination therapy of Alpelisib and an aPKC inhibitor for metastatic ccRCC can reduce expression of multi drug resistance (MDR) proteins/efflux transporter P-gp and ABCG2. Therefore, a combination of Alpelisib and an aPKC inhibitor is an effective approach to reducing cell proliferation, invasion and resistance eventually inducing apoptosis.

Citation Format: Khandker Mohammad Khalid, Wishrawana S. Ratnayake, Christopher A. Apostolatos, Luke Lajmi, Sloan Breedy, Nuzhat N. Oishee, Mildred Acevedo-Duncan. A combination therapy of atypical protein kinase C inhibitors and phosphatidylinositol-3-kinase inhibitor reduces resistance & invasiveness in renal cell carcinoma (RCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 158.