Targeting MYC-Driven Mantle Cell Lymphoma with the Multifaceted Inhibitor LCI139: Overcoming Drug Resistance and Enhancing Therapeutic Potential

Mantle cell lymphoma (MCL) is an aggressive B cell cancer characterized by a specific chromosomal translocation that causes overexpression of Cyclin D1 and disruption of the cell cycle. Typically diagnosed at advanced stages, MCL has a poor prognosis with a median survival of 2.5-5 years despite initial responses to chemotherapy. The development of resistance to single-agent targeted therapies is a significant challenge in treating relapsed/refractory MCL.

To address this issue, the multitarget small molecule inhibitor LCI139 was developed using in-silico methods, designed to inhibit three oncogenic targets: CDK9, CDK4/6, and PI3K. LCI139 showed potent inhibitory activity against these targets with very low IC50 values, demonstrating high selectivity over wildtype KRAS.

In a panel of MCL cell lines, LCI139 exhibited strong cytotoxic effects with maximal IC50 values in the nanomolar range for JeKo-1, Mino, and Rec-1 cells. Compared to the single-agent CDK9 inhibitor AZD4573, LCI139 displayed lower toxicity to normal human stromal cells. It induced significant apoptosis in JeKo-1 and Mino cells at concentrations of 100 nM and 200 nM, as evidenced by Annexin V/7-AAD staining and increased cleaved-PARP protein levels.

LCI139 induced cell cycle arrest, with G2/M phase inhibition in JeKo-1 cells and G1 phase arrest in Mino cells. It also significantly reduced the expression of MCL-1 and MYC mRNA and protein in a short-term exposure, suggesting a mechanism involving the downregulation of anti-apoptotic proteins and inhibition of transcriptional CDKs. The compound decreased the stability and half-life of MCL-1 and cMYC proteins, with a decrease in cMYC stability associated with reduced phosphorylation at Ser62.

RNA sequencing analysis revealed that LCI139 overcomes ibrutinib resistance, as shown by its ability to decrease viability in ibrutinib-resistant MCL cell lines with low IC50 values.

In conclusion, LCI139 has demonstrated superior potency against MCL cell lines, including those resistant to ibrutinib, by exhibiting cytotoxic effects, inducing apoptosis, and overcoming resistance at nanomolar doses. These findings indicate the potential of LCI139 as a novel therapeutic agent for MCL.