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Serial single-cell genomics reveals convergent subclonal evolution of resistance as early-stage breast cancer

Jason I Griffiths1,2, Jinfeng Chen1,3, Patrick A Cosgrove1

  • 1Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA.

Nature Cancer
|October 29, 2021
PubMed

Insights

Combining CDK inhibitors with endocrine therapy for early-stage ER+ breast cancer can lead to resistance. Tumors shift from estrogen signaling to alternative growth pathways, like JNK and ERK signaling, to proliferate.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genomics

Background:

  • Endocrine therapy combined with CDK inhibitors benefits metastatic ER+ breast cancer.
  • The efficacy of this combination in earlier stages of ER+ breast cancer remains uncertain.

Purpose of the Study:

  • To investigate the evolutionary dynamics of early-stage ER+ breast cancer tumors under different treatment regimens.
  • To identify resistance mechanisms emerging from combination therapy (letrozole + ribociclib) versus endocrine therapy alone.

Main Methods:

  • Single-cell RNA sequencing (scRNAseq) of serial tumor biopsies from the FELINE clinical trial (NCT02712723).
  • Analysis of tumor evolutionary trajectories and subclonal diversity in response to letrozole and ribociclib treatments.

Main Results:

  • Common resistance phenotypes emerged despite patient-specific evolutionary differences.
  • Combination therapy accelerated estrogen signaling loss and induced JNK signaling via growth factor receptors.
  • Tumors maintaining estrogen signaling showed increased CDK4/6 and ERK activation via ERBB4 signaling.

Conclusions:

  • Combination therapy in early-stage ER+ breast cancer drives resistance by shifting proliferation signals.
  • Tumors adapt by transitioning from estrogen dependence to alternative growth factor-mediated pathways.

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