While eliminating cranial irradiation has dramatically improved survival and neurocognitive and neuroendocrine outcomes in this population, clinically significant hearing loss is now the leading late effect due to the necessity of platinum-based chemotherapy. Our results document the need for audiometric monitoring and developing otoprotective strategies in this vulnerable population.

We describe a case of Pneumocystis jirovecii pneumonia in an 18-year-old female individual with refractory primary mediastinal B-cell lymphoma treated with the immune checkpoint inhibitor pembrolizumab. She received 11 doses of pembrolizumab without immune-related adverse events (irAEs) before the diagnosis of P. jirovecii pneumonia. However, prophylactic trimethoprim/sulfamethoxazole was discontinued 6 months of postautologous stem cell transplant per standard guidelines. This case report highlights the importance of judicious infectious disease evaluation while on immune checkpoint inhibitor therapy as symptoms can often mimic irAEs. Furthermore, the benefits of immunosuppressive therapy for the treatment of presumptive irAEs must be weighed against the possible increased risk for opportunistic infections.

Cutaneous melanoma is a highly invasive skin cancer. Mortality for melanoma is low if caught before metastasis occurs, but is poor if metastasis has occurred at diagnosis. Melanomas are among the most mutated cancer genomes and have a high neoantigen load, which is related to better response to immunotherapies. A subset of melanomas contains mutations in BRAF(V600E) and respond initially to BRAF inhibitors, though they become resistant through escape pathways. Focused development of BRAF and immunotherapies has resulted in the clinical use of targeted therapies against the oncogenic BRAF/MEK/ERK pathway and immune checkpoint inhibitors for the treatment of metastatic melanoma. Although some patients with metastatic melanoma benefit from these therapies, others either do not respond or become resistant. Because of this, new targets and drugs are needed for patients who are either intrinsically resistant or have acquired resistance to targeted therapies and immunotherapies. RSKs are serine/threonine kinases downstream of BRAF/ERK that activate transcription, proliferation and cell survival. Thus RSKs are potential new targets and the availability of a RSK inhibitor called PMD-026, now in Phase 1b clinical trials for breast cancer, provides a tool to explore this possibility in pre-clinical models of melanoma. PMD-026 is an ATP-competitive inhibitor of the N-terminal kinase domain. This inhibitor is highly stable and effective in cell-based assays with an average IC50 of 2nM and 200-400 nM in soft agar and inhibits tumor growth in multiple mouse models of breast cancer given 70-100 mg/kg given orally. It is currently the only RSK inhibitor that can be given to mice orally with demonstrated in vivo activity. To explore the opportunity for RSK inhibitors in melanoma, we screened 1,959 PDx models for RSK1-4 expression, which was evaluated based on RNAseq. In melanoma, RSK1 and RSK2 were highly expressed, unlike RSK3 and RSK4. In a study of 21 cases of melanoma, RSK2 was activated in 52% of the cases based on nuclear localization using our companion diagnostic. Using FRET based assays, PMD-026 inhibited RSK2 binding with an IC50=14 nM compared to BID1870 with IC50=94 nM demonstrating competitive in vitro potency. Importantly, PMD-026 inhibits viability of melanoma cells including those that are resistant to the BRAF inhibitor. Surprisingly, we also found that it significantly reduces PD-L1 expression at the cell surface of several melanoma lines. This is through down-regulation of PD-L1 transcription and subsequent reduced PD-L1 cell surface expression. As expected, in our melanoma models, PMD-026 inhibited RSK signaling through pYB-1, a transcription factor known to bind to the PD-L1 promoter. Testing in pre-clinical mouse models is in progress. We propose that PMD-026 may therefore potentiate melanoma immunotherapy approaches and also improve response of patients to BRAFV600E targeted therapies. Citation Format: Joe William Ramos, Stephanie Si, Takeo Fujii, Brien Haun, Won Seok Yang, Aarthi Jayanthan, Sandra E. Dunn. Targeting B-RAF and checkpoint inhibitor resistant melanoma with RSK inhibitor PMD-026 in pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1218.