The pathways leading to CDK4/6 inhibitor resistance are not yet clear. Using a technique called ‘accelerated mutagenesis’, researchers unraveled the role of ASXL1 loss. Initial findings in ER-positive breast cancer cell lines are confirmed in tumors from patients.

CDK4/6 inhibitors in combination with anti-estrogens have prolonged survival of patients with ER-positive/HER2-negative metastatic breast cancer. However, this combination is not curative mainly due to acquired drug resistance. Knowledge about mechanisms of such resistance remains quite incomplete. Dr. Dhivya Sudhan (UT Southwestern Medical Center, TX, USA) reported results of new insights in the pathways leading to CDK4/6 inhibitor resistance [1]. Using CRISPR/Cas9 to delete the DNA mismatch repair gene MSH2 in MCF7 and T47D ER-positive breast cancer cell lines, Dr. Sudhan and colleagues obtained cells with drug resistance-associated mutations. Clones resistant to CDK4/6 inhibitors were selected and subjected to whole exome sequencing. Of the 10 genes recurrently mutated in the CDK4/6 inhibitor-resistant cells, loss of ASXL1 was identified as top hit. ASXL1 encodes a polycomb repressive complex protein that regulates chromatin accessibility. Loss of ASXL1 has been implicated in myeloid transformation through epigenetic reprogramming. In line with these findings, among 1,769 tumors from patients treated with CDK4/6 inhibitor (TEMPUS database), 37 exhibited ASXL1 alterations (4 frameshift, 6 truncating, 3 in-frame deletion, 24 missense mutations). In addition, RNA sequencing of patient-derived organoids established from post-CDK4/6 inhibitor metastases identified ASXL1 mutations in 2/7 organoids (29%). Functional studies showed that loss of ASXL1 was associated with maintenance of RB phosphorylation in the presence of CDK4/6 inhibition, markedly higher levels of CDK2, CDK6, cyclins E and A, and downregulation of p21 and p27. “Using MMR-deficient, ER-positive breast cancer cells, we identified loss of ASXL1 as a novel mechanism of resistance to CDK4/6 inhibition,” concluded Dr. Sudhan. “ASXL1 alterations were found in ~8% of tumors from patients with de novo or acquired resistance to CDK4/6 inhibitors. Knockdown of CDK2 and cyclin A restored sensitivity to CDK4/6 inhibitors and reduced viability of ASXL1-deficient cells, suggesting CDK2 inhibitors are a treatment approach against these drug-resistant tumors.”

  1. Sudhan DR, et al. Loss of ASXL1 tumor suppressor promotes resistance to CDK4/6 inhibitors in ER+ breast cancer. SABCS 2021 Virtual Meeting, abstract GS3-09.

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