PRMT5 Inhibitors Plus Antiestrogens May Combat Resistance to CDK4/6 Inhibitors in ER+ Breast Cancer

Combining protein arginine methyltransferase 5 (PRMT5) inhibitors with antiestrogens represents a novel therapeutic strategy that may overcome resistance to CDK4/6 inhibitors in estrogen receptor (ER)-positive, retinoblastoma protein (RB)-deficient breast cancer, according to Carlos L. Arteaga, MD.¹

In a presentation at the 41st Annual Miami Breast Cancer Conference^®, Arteaga noted that although CDK4/6 inhibitors in combination with antiestrogens have prolonged survival for patients with ER-positive breast cancer, patients who experience disease progression on CDK4/6 inhibitors are left with few options. Additionally, CDK4/6 inhibitors require RB to exert their antitumor effort.

“To identify actionable vulnerabilities in this refractory breast cancer genotype, we performed a genome-wide CRISPR screen using ER-positive, RB1-knockout cells and identified PRMT5 as a novel dependence in these cells,” Arteaga said. “A second mechanism of endocrine resistance and early escape from CDK4/6 inhibitors is activating mutations in the HER2 gene. The irreversible pan-HER2 TKI neratinib [Nerlynx] has demonstrated clinical activity in HER2-mutant, ER-positive metastatic breast cancer, particularly in combination with endocrine therapy,” Arteaga added. He is the director of the Simmons Comprehensive Cancer Center, associate dean of Oncology Programs at UT Southwestern Medical Center, and the Annette Simmons Distinguished University Chair in Breast Cancer Research.

The CRISPR screen identified PRMT5 as an essential gene in ER-positive, RB1-knockout (RBKO) cells, showing that PRMT5 silencing completely arrests ER-positive/RBKO cell proliferation. Preclinical data also revealed the PRMT5 inhibitor pemrametostat suppresses symmetric dimethylarginine levels and inhibits ER-positive/RBKO cell viability. The agent in combination with fulvestrant (Faslodex) demonstrated synergistic activity against ER-positive, RB1-deficient breast cancer xenografts (n = 8 to 10) as well as molecular target inhibition in vivo.²

PRMT5 Inhibitors Under Development

Non-selective PRMT5 inhibitors in development include pemrametostat which is under evaluation in the active phase 1/2 METEOR-1 trial (NCT02783300) for patients with solid tumors and non-Hodgkin lymphoma (NHL). A phase 1 trial (NCT03886831) examining the agent PRT543 was recently completed in patients with relapsed or refractory advanced solid tumors or diffuse large B-cell lymphoma. JNJ-64619178 is being evaluated in an active phase 1 study (NCT03573310) in adult solid tumors and neoplasms, and a phase 1 study (NCT04089449) examining PRT811 was recently completed. Additionally, a phase 1 study (NCT05528055) is currently enrolling patients with solid tumors and NHL to receive SCR-6920.¹

However, several trials looking at non-selective PRMT5 inhibitors have been terminated, including a phase 2 study in patients with acute myeloid leukemia or myelodysplastic syndrome with pemrametostat (NCT03614728) and a phase 1 study (NCT03854227) of PF-06939999 in advanced or metastatic solid tumors.

PRMT5 inhibitors targeting MTA in MTAP del cancers that are currently recruiting patients, all in phase 1/2 studies, are AMG193 (advanced MTAP-null solid tumors; NCT05094336), MRTX1719 (mesothelioma and NSCLC; NCT05245500), and TNG462 (NCT05732831) and TNG908 (NCT05275478) in locally advanced solid tumors.

Finally, the MAT2A inhibitor IDE397 is under evaluation in a phase 1 study (NCT04794699) for patients with solid tumors.¹

HER2 Mutations and Resistance to Endocrine Therapies

Research including 1365 samples from patients (n = 1116) with ER-positive metastatic breast cancer at Memorial Sloan Kettering Cancer Center demonstrated that HER2 mutations without HER2 gene amplification are associated with antiestrogen resistance.³

“I was able to generate this plot in patients with metastatic disease who presumably have progressed after primary endocrine therapy,” Arteaga said regarding the Memorial Sloan Kettering Cancer Center data. “Mutations in HER2 happen in approximately 8% of tumors and they do not overlap with other alterations associated with endocrine resistance such as NF1, KRAS, loss of RB1, or FGFR1 amplification. These mutations occur in up to 8% of advanced ER-positive breast cancers, [2%] of primary disease, and approximately 10% to 15% of metastatic invasive lobular carcinomas express these mutations. Most of them are ER-positive and they happen in the absence of HER2 gene amplification. I want to emphasize that these tumors are clinically HER2 negative.”

Arteaga also noted that HER2 mutations occur across multiple domains of the protein including the kinase, extracellular, and transmembrane domains. The most common variants are single nucleotide variants in the kinase domain, exon 20 insertions, and S310F/Y in the extracellular domain. Arteaga added that common comutations include TP53, PIK3CA, ERBB3, and CDH1.¹

He also noted that although patients with ER-positive, HER2-mutant breast cancer experienced greater benefit with the combination of fulvestrant and neratinib, acquired secondary HER2 mutations are associated with resistance to neratinib in ER-positive disease. Data revealed that certain HER2-mutant cancers that became resistant to the combination therapy acquired amplification of the mutant allele.⁴ Additionally, it’s been shown that acquired secondary HER2L755S and HER2T862A mutations cause resistance to the agent.⁵

“Unlike HER2/HER3 mutants, which mainly induce PI3K/AKT, HER2 double mutants hyperactivate both PI3K/AKT and MEK/ERK pathways,” Arteaga said. Data has also shown that HER2 double mutants show reduced sensitivity to the majority of HER2 TKI agents but are sensitive to inhibition with HER2 and MEK agents together.^1,5

Investigators have hypothesized that adding trastuzumab (Herceptin) to treatment with fulvestrant and neratinib may be beneficial for patients with HER2-mutant advanced breast cancer.⁶ Updated NCCN guidelines recommend both the doublet and triplet in the treatment of ER-positive, HER2-mutant breast cancer under category 2B evidence when patients have already received CDK4/6 inhibitor therapy.⁷

Furthermore, because rates of pathologic complete response to chemotherapy or endocrine therapy alone are low in invasive lobular breast cancer, investigators plan to combine neratinib and letrozole in an upcoming neoadjuvant trial in patients with HER2-mutant disease.¹

“Neoadjuvant treatment of patients with early-stage operable HER2-mutant invasive lobular breast cancer with HER2 TKIs may significantly impact patient outcomes without disrupting current standards of care,” Arteaga said.

References

1. Arteaga C. Giants of cancer care lecture: Resistance to CDK4/6 inhibitors in ER+ breast cancer. Presented at: 41st Annual Miami Breast Cancer Conference; March 7-10, 2024; Miami, Florida. Accessed March 8, 2024.
2. Lin CC, Chang TC, Wang Y, et al. Protein arginine methyltransferase 5 (PRMT5) is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer. Res Sq [Preprint]. 2023:rs.3.rs-2966905. doi:10.21203/rs.3.rs-2966905/v1
3. Li Q, Jiang B, Guo J, et al. INK4 tumor suppressor proteins mediate resistance to CDK4/6 kinase inhibitors. Cancer Discov. 2022;12(2):356-371. doi:10.1158/2159-8290.CD-20-1726
4. Smyth LM, Piha-Paul SA, Won HH, et al. Efficacy and determinants of response to HER kinase inhibition in HER2-mutant metastatic breast cancer. Cancer Discov. 2020;10(2):198-213. doi:10.1158/2159-8290.CD-19-0966
5. Marín A, Mamun AA, Patel H, et al. Acquired secondary HER2 mutations enhance HER2/MAPK signaling and promote resistance to HER2 kinase inhibition in breast cancer. Cancer Res. 2023;83(18):3145-3158. doi:10.1158/0008-5472.CAN-22-3617
6. Jhaveri K, Eli LD, Wildiers H, et al. Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial. Ann Oncol. 2023;34(10):885-898. doi:10.1016/j.annonc.2023.08.003
7. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 1.2024. Accessed March 8, 2024. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf