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Concomitant MEK and Cyclin Gene Alterations: Implications for Response to Targeted Therapeutics

Shumei Kato1, Jacob J Adashek2, Justin Shaya3

  • 1Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, UC San Diego Moores Cancer Center, La Jolla, California. smkato@ucsd.edu.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|January 21, 2021
PubMed
Abstract

Insights

Combination therapy targeting cyclin-dependent kinases 4/6 (CDK4/6) and the MEK pathway shows promise for advanced cancers with specific genetic alterations. This approach may overcome resistance seen with single-agent treatments.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Alterations in cyclin and MAPK/MEK pathways are crucial for cell-cycle progression and cancer development.
  • Monotherapy targeting CDK4/6 or MEK pathways often shows limited efficacy.
  • Co-occurring alterations in cyclin and MEK pathway genes suggest a potential for combination therapy.

Purpose of the Study:

  • To investigate the efficacy of combining CDK4/6 and MEK inhibitors in patients with advanced malignancies.
  • To test the hypothesis that targeting both pathways can overcome resistance mediated by oncogenic co-drivers.

Main Methods:

  • Treatment of 9 patients with advanced cancers harboring co-occurring alterations in CDKN2A/CDKN2B (upregulating CDK4/6) and KRAS/BRAF (activating MEK pathway).
  • Combination therapy using palbociclib (CDK4/6 inhibitor) and trametinib (MEK inhibitor).

Main Results:

  • Two patients (pancreatic cancer) achieved partial remission.
  • Overall, 56% of patients (5/9) demonstrated clinical benefit, defined as stable disease for ≥ 6 months or partial remission.
  • Progression-free survival ranged from approximately 7 to 17.5+ months, with one patient showing significant benefit after adding palbociclib to a prior MEK inhibitor regimen.

Conclusions:

  • Cotargeting cyclin and MEK signaling is a viable strategy for tumors with genomic alterations activating both pathways.
  • This precision medicine approach shows potential for overcoming therapeutic resistance.
  • Further prospective studies are warranted to validate these findings.

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