RSK Inhibition Is Poised for Deeper Activity in RSK-High, CDK4/6 Inhibitor–Resistant Breast Cancer

By inhibiting RSK at the intersection of key pathways for tumor growth, the investigational agent PMD-026 is hypothesized to disrupt tumor proliferation and suppress estrogen receptor (ER) signaling, offering a potential strategy to overcome CDK4/6 inhibitor resistance in breast cancers with high RSK expression.

“Patients with breast cancer who have high RSK expression have been shown to have poor survival compared with [those who] have low RSK expression,” Hung Khong, MD, said in an interview with OncLive. “We want to focus on the population who has a poor prognosis.”

Khong is a breast medical oncologist at Banner MD Anderson Cancer Center, part of Banner Health, in Gilbert, Arizona.

Why target RSK in breast cancer?

RSK is located at the conjunction point between the PI3K and ERK-MAPK pathways, which Khong noted are involved in cell proliferation.¹

“When a cell has high RSK expression, it has higher proliferation and survival rates,” Khong said. “Data have shown that [RSK] is involved in the DNA damage repair [DDR] pathway as well.”

Prior reports have shown that approximately 70% of breast tumors highly express RSK2 regardless of subtype, which has been shown to be associated with poor prognosis in this disease.²

Research in mouse models has shown that RSK2 binds directly to ERα, which advances tumor development and growth.³ Additionally, RSK1 through RSK4 are associated with tumor resistance to endocrine therapy and CDK4/6 inhibitors.²

RSK steers treatment resistance by promoting the G₂/M phase of the cell cycle and avoiding control signals from the G₁/S phase.

By inhibiting RSK, the first-in-class oral small molecule PMD-026 reduces ER transcription, thereby limiting cell proliferation, cell growth, and potentially DDR, Khong explained. This agent has been shown to stop G₂/M progression and block tumor growth in preclinical models of CDK4/6 inhibitor–resistant cells.

“In the context of ER-positive cancer cells, [PMD-026] in combination with an antiestrogen molecule has synergism in inhibition of cell growth and proliferation,” Khong said.

A study in an ESR1 wild-type, hormone receptor–positive MCF7 cell line showed that the addition of PMD-026 to fulvestrant (Faslodex) reduced ERα transcription by 84%. These findings led to the hypothesis that combining PMD-026 and fulvestrant is an effective strategy for overcoming CDK4/6 inhibitor resistance in patients with metastatic breast cancer.

What were the key findings from the phase 1 portion of Dauntless-1?

The single-arm, open-label, first-in-human phase 1 portion of the Dauntless-1 trial (NCT04115306) enrolled patients with metastatic triple-negative breast cancer (TNBC) who had measurable disease per RECIST v1.1 criteria and disease progression during or following standard-of-care treatment.⁴ The primary end point of this portion was safety. Secondary end points included clinical activity, pharmacokinetics (PK), and correlative biomarker analyses.

During dose expansion, patients received PMD-026 monotherapy at 200 mg twice daily in 21-day cycles, following the dose-escalation portion that identified the recommended phase 2 dose (RP2D) of 200 mg taken orally every 12 hours, based on plasma exposure findings showing targeted preclinical efficacious concentrations at this dose level.

Among heavily pretreated patients with metastatic breast cancer (n = 41) who received PMD-026 at the escalation doses of 25 to 200 mg daily or 200 mg to 300 mg every 12 hours, or the RP2D, the most common grade 3 treatment-related adverse effects (TRAEs) included increased aspartate aminotransferase (AST) levels (12%) and increased alanine aminotransferase (ALT) levels (7%), both of which were normalized with dose reductions. Additionally, fatigue (7%), decreased lymphocyte count (5%), and dehydration (2%) were also reported.⁵ No grade 4 TRAEs were reported.

Among patients evaluable for tumor response (n = 30) across dose levels, the median prior number of therapies was 5, the disease control rate (DCR) was 40%, and 20% of patients experienced measurable tumor reductions. The best response was observed in patients with de novo TNBC and high RSK2 expression, defined as a histochemical score (H-score) of at least 140 (n = 10), all of whom received the RP2D; in this population, the DCR was 70%, and 40% of patients experienced measurable tumor reductions. Of patients with de novo TNBC regardless of RSK2 expression treated at the RP2D (n = 17), these respective rates were 53% and 24%. Of patients with TNBC with de novo or secondary disease (hormone receptor–positive disease refractory to CDK4/6 inhibition) who received the RP2D (n = 26), these rates were 38% and 23%, respectively. Among patients with de novo or secondary TNBC with high RSK2 expression (n = 15), these rates were 53% and 40%, respectively.

The median progression-free survival (PFS) was significantly longer in patients who had received 5 or fewer prior lines of therapy than in those who had received more than 5 (HR, 0.19; 95% CI, 0.06-0.52; P = .0014). Additionally, the median PFS among patients who had received 5 or fewer prior lines and had an RSK2 H-score of at least 140 was longer at 4.3 months vs 1.3 months among those with low RSK2 expression (HR, 0.12; 95% CI, 0.02-0.06; P = .0075). Among patients who had received more than 5 prior lines and had an RSK2 H-Score of at least 180, the median PFS was 4.8 months vs 1.3 months among those with a lower H-Score (HR, 0.07; 95% CI, 0.02-0.36; P = .0012).

“That’s the reason we’re doing a study in the phase 2 setting now, because the phase 1 study showed a benefit in the RSK2-high population,” Khong said. “The initial preclinical and phase 1 studies focused on TNBC, but because of the synergy seen in preclinical data with the selective ER degrader [SERD] fulvestrant, the focus right now is mainly on ESR1 wild-type breast cancer.”

What is the design of the phase 2a portion of Dauntless-1?

The single-arm portion of the trial is enrolling patients with RSK2-positive, hormone receptor–positive, HER2-negative, ESR1 wild-type locally advanced or metastatic breast cancer that is not amenable to curative-intent resection, radiation, or systemic therapy.⁶ Patients must be eligible to receive endocrine therapy and have previously received at least 1 line of endocrine therapy for metastatic breast cancer or had disease recurrence during treatment with adjuvant endocrine therapy for locally advanced disease. Endocrine therapy must be discontinued at least 15 days before the first dose of PMD-026. Patients also need to have progression on or after treatment with a CDK4/6 inhibitor plus endocrine therapy in the locally advanced or metastatic setting. Patients are receiving PMD-026 in combination with fulvestrant.

Safety/tolerability is the primary end point. Secondary end points include PK and antitumor activity. Overall survival, QT interval, and PMD-026 concentrations are additional end points.

What findings have been seen in the phase 2 portion of Dauntless-1 so far?

The trial initially studied PMD-026 at 2 dose levels: 200 mg every 12 hours (the RP2D from the phase 1 portion) and 100 mg every 12 hours.² Both evaluable patients who had received 2 doses of PMD-026 at the 200-mg dose developed grade 3 AST and ALT level increases as well as grade 3 maculopapular rash. Conversely, among 6 evaluable patients who received the investigational agent at the 100-mg dose, the only grade 3 TRAE observed was maculopapular rash in 1 patient. Therefore, the study investigators reduced the starting dose of PMD-026 to 100 mg twice daily. This starting dose reduction was further supported by PK findings showing that plasma levels of PMD-026 still fell within the range for synergy with fulvestrant in 1 patient treated at the 100-mg dose.

Preliminary efficacy findings showed early and durable antitumor activity of PMD-026 plus fulvestrant in the phase 2 population, with treatment durations in certain patients exceeding the 2.35-month historical median PFS observed with fulvestrant monotherapy.

“There are a lot of options for patients with ESR1 mutations because we have an oral SERD [elacestrant (Orserdu)] approved for [use in this population],” Khong said. “However, there are limited options for patients with ESR1 wild-type [disease because ESR1 is] the gene encoding the ER. Therefore, the future development [of PMD-026] will be focused on patients with ESR1 wild-type disease. That’s the largest [breast cancer subtype] population that we have, because ESR1 mutations are only seen in approximately 40% of patients. The other 60% of patients will be the focus of the future development [of PMD-026].”

In what other disease types is RSK inhibition being evaluated?

Preclinical research in human B-cell lymphoma–derived cell lines has also demonstrated the potential for RSK inhibition across subtypes of this disease.⁷ Results from a study found that blockade of the master kinase PDPK1 led to cell cycle arrest, growth inhibition, and apoptosis in 8 B-cell lymphoma–derived cell lines. Additionally, RSK2 was identified as one of a few major downstream therapeutic targets of PDPK1 and as a downstream effector of the kinase, promoting cell survival and proliferation.

Based on these findings, investigators studied the activity of the RSK/AKT/S6K inhibitor TAS0612. This agent demonstrated antilymphoma activity in 8 B-cell lymphoma–derived cell lines and in 25 patient-derived B-cell lymphoma cells across disease subtypes. In all these cells, TAS0612 downregulated mTOR and MYC target genes and induced the tumor suppressor protein TP53INP1. Taken together, these findings support simultaneous RSK2/AKT/S6K blockade as a novel therapeutic strategy, particularly via the future clinical development of TAS0612, for the management of B-cell lymphoma.

“We never had an RSK inhibitor before,” Khong said. “Therefore, it’s exciting to see anything new. Anything new for patients gives them more options in terms of treatment and hopefully prolongs their survival and improves their quality of life.”

References

1. Spirrison AN, Lannigan DA. RSK1 and RSK2 as therapeutic targets: an up-to-date snapshot of emerging data. Expert Opin Ther Targets. 2024;28(12):1047-1059. doi:10.1080/14728222.2024.2433123
2. Khong HT, Beeram M, Wesolowski R, et al. Dauntless-1: a phase 2 clinical trial to evaluate PMD-026, a first-in-class pan-RSK inhibitor, combined with fulvestrant to overcome resistance to CDK4/6 inhibitors in advanced or metastatic HR+/HER2- breast cancer. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract PS1-08-15.
3. Clark DE, Poteet-Smith CE, Smith JA, Lannigan DA. Rsk2 allosterically activates estrogen receptor alpha by docking to the hormone-binding domain. EMBO J. 2001;20(13):3484-3494. doi:10.1093/emboj/20.13.3484
4. Beeram M, Chalasani P, Wang JS, et al. First-in-human phase 1/1b expansion of PMD-026, an oral RSK inhibitor, in patients with metastatic triple-negative breast cancer. J Clin Oncol. 2021;39(suppl 15):e13043. doi:10.1200/JCO.2021.39.15_suppl.e13043
5. Wang JS, Beeram M, Chalasani P, et al. High levels of RSK2 in breast cancer patients is associated with longer PFS in patients treated with PMD-026, a first in class RSK inhibitor. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract P4-01-16.
6. Phase 1/​1b/​2 study of oral PMD-026 in patients with metastatic breast cancer (Dauntless-1). ClinicalTrials.gov. Updated January 21, 2026. Accessed March 13, 2026. https://clinicaltrials.gov/study/NCT04115306
7. Katsuragawa-Taminishi Y, Mizutani S, Kawaji-Kanayama Y, et al. Triple targeting of RSK, AKT, and S6K as pivotal downstream effectors of PDPK1 by TAS0612 in B-cell lymphomas. Cancer Sci. 2023;114(12):4691-4705. doi:10.1111/cas.15995