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Blocking Genomic Instability Prevents Acquired Resistance to MAPK Inhibitor Therapy in Melanoma

Prashanthi Dharanipragada1, Xiao Zhang1, Sixue Liu1

  • 1Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.

Cancer Discovery
|January 26, 2023
PubMed

Insights

Blocking cancer genomic instability, particularly nonhomologous end-joining (NHEJ) gene amplification, can prevent melanoma resistance to MAPK inhibitor (MAPKi) therapy. Targeting NHEJ reduces complex genomic rearrangements (CGRs) and extrachromosomal DNAs (ecDNAs), delaying acquired resistance.

Area of Science:

  • Genomics
  • Cancer Biology
  • Molecular Oncology

Background:

  • Cancer genomic instability drives tumor evolution and therapeutic escape.
  • Acquired resistance to targeted therapies like MAPK inhibitors (MAPKi) is a major clinical challenge.
  • Metastatic cutaneous melanoma often develops resistance through complex genomic alterations.

Purpose of the Study:

  • To investigate the genomic mechanisms underlying acquired resistance to MAPKi in melanoma.
  • To identify potential therapeutic targets for preventing or overcoming MAPKi resistance.
  • To evaluate the role of nonhomologous end-joining (NHEJ) in driving genomic instability and resistance.

Main Methods:

  • Analysis of patient-derived xenografts (PDX) and human melanoma cell lines treated with MAPKi.
  • Whole-genome sequencing to identify complex genomic rearrangements (CGRs) and extrachromosomal DNAs (ecDNAs).
  • Assessment of DNA repair gene amplification (NHEJ and HRR) in sensitive and resistant tumors.
  • Pharmacological inhibition of DNA-PKCS, a key component of NHEJ, in combination with MAPKi.

Main Results:

  • Acquired resistance to MAPKi in melanoma is associated with amplification of NHEJ and homologous recombination repair (HRR) genes via CGRs and ecDNAs.
  • Chromothriptic regions, ecDNAs, and CGRs are pervasive in both sensitive and resistant melanoma genomes.
  • NHEJ is critical for the formation of CGRs and ecDNAs, as indicated by breakpoint-junctional sequence analysis.
  • Inhibition of DNA-PKCS/NHEJ delays acquired MAPKi resistance by reducing ecDNA and CGR formation.

Conclusions:

  • Targeting genomic instability, specifically NHEJ-mediated CGR and ecDNA formation, is a promising strategy to prevent acquired resistance to MAPKi in melanoma.
  • Chromothripsis-ecDNA-CGR biogenesis represents a key mechanism of resistance that can be therapeutically targeted.
  • Combination therapy with MAPKi and NHEJ inhibitors may overcome or prevent therapeutic resistance in melanoma.

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