Biology subjects

Alluri, P. G.

Publications and source records attributed to Alluri, P. G..

2 recordsLinked to original sources

bioRxiv2026

Radiation synergizes with BET inhibition to stimulate durable, systemic anti-tumor immunity in murine cancer models

Most patients with breast cancer (BC) and soft tissue sarcoma (STS) harbor immunologically cold tumors and do not respond to existing immunotherapies such as immune checkpoint inhibitors (ICIs) as a monotherapy. Consequently, prolonged treatment with highly toxic multiagent chemotherapy, with or without ICIs, remains the mainstay of systemic therapy in such patients. Therefore, there is an acute clinical need for novel chemotherapy-free immunotherapy regimens with high efficacy and minimal toxicity. Here, employing an in vivo drug screen, we identify that a short course of radiation therapy (RT) synergizes with pharmacological bromodomain and extraterminal (BET) inhibition to elicit a strong systemic anti-tumor immunity and long-term immunological memory in a CD8+ T cell-dependent manner in murine models of both BC and STS. Mechanistic studies reveal that RT + BET inhibition accentuates RT-induced DNA damage and micronuclei formation, increases Major Histocompatibility Complex class I and II expression on macrophages, enhances translocation of calreticulin to the plasma membrane, and blocks RT-induced Programmed Death-Ligand 1 (PD-L1) overexpression on tumor cells, thereby promoting immunogenic cell death. Our data suggest that a combination of RT + BET inhibition promotes robust anti-tumor immunity and immunological memory in immunologically cold tumors, thereby opening potential avenues for clinical translation.

immunology↗

bioRxiv2025

The non-kinase function of CDK6 is a key driver of acquired resistance to CDK4/6 inhibitors in Estrogen Receptor-positive breast cancer

The therapeutic efficacy of CDK4/6 inhibitors in ER+ breast cancer (BC) patients is presumed to arise from inhibition of the kinase function of CDK4 and 6 proteins. Despite their initial efficacy, development of acquired resistance to CDK4/6 inhibitors in metastatic ER+ BC patients is nearly universal, commonly through compensatory overexpression of CDK6. Here, we show that primary ER+ tumors show high CDK4 but very low to undetectable expression of CDK6, which suggests that the therapeutic efficacy of CDK4/6 inhibitors in ER+ BC patients is largely driven by inhibition of CDK4, rather than CDK6. Furthermore, we show that overexpression of CDK6 confers acquired resistance to CDK4/6 inhibitors, largely, through a kinase-independent function. Our findings challenge the dogma that CDK4/6-mediated phosphorylation of retinoblastoma protein (pRB) is necessary to ER+ BC cells to progress from G1 to S phase of cell cycle. Consequently, by taking advantage of the non-kinase function of CDK6, ER+ BC cells acquire independence from the kinase function of CDK4 and 6 for cell cycle progression. These findings highlight the limitations of the current standard-of-care treatments, which focus on merely inhibiting the kinase function of CDK4 and 6, and uncover the non-kinase function of CDK6 as a new targetable vulnerability to overcome acquired resistance to CDK4/6 inhibitors in ER+ BC.

cancer biology↗