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Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
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PIK3CA Mutations Contribute to Acquired Cetuximab Resistance in Patients with Metastatic Colorectal Cancer

Jian-Ming Xu1, Yan Wang2, You-Liang Wang3

  • 1Affiliated Hospital Cancer Center, Academy of Military Medical Sciences, Beijing, China. jmxu2003@yahoo.com.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|April 21, 2017
PubMed

Insights

New PIK3CA mutations may drive acquired resistance to cetuximab in metastatic colorectal cancer (mCRC). These findings suggest PIK3CA mutations, alongside KRAS, are key in understanding treatment resistance in mCRC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • KRAS mutations are primary drivers of acquired resistance to epidermal growth factor receptor (EGFR) blockade in metastatic colorectal cancer (mCRC).
  • The role of other downstream EGFR pathway genes in acquired resistance remains under-investigated.

Purpose of the Study:

  • To investigate potential novel genetic drivers of acquired cetuximab resistance in mCRC beyond KRAS.
  • To screen for low-abundance somatic mutations in EGFR signaling pathway genes using circulating tumor DNA (ctDNA).

Main Methods:

  • Developed a targeted amplicon ultra-deep sequencing method for ctDNA analysis in mCRC patients with acquired cetuximab resistance.
  • Screened a panel of EGFR pathway genes, selecting mutations with increased variant frequencies upon progression using quartile analysis.
  • Validated functional consequences of identified mutations in cell culture models.

Main Results:

  • Identified five novel PIK3CA mutations (p.K944N, p.F930S, p.V955G, p.V955I, p.K966E) in 22% of patients with acquired resistance.
  • Novel PIK3CA mutations in exon 19 promoted cell viability despite cetuximab treatment.
  • Patients with PIK3CA or RAS mutations in ctDNA exhibited significantly reduced progression-free survival compared to those without mutations.

Conclusions:

  • PIK3CA mutations represent a potential mechanism contributing to acquired cetuximab resistance in mCRC.
  • These findings expand the understanding of genetic alterations driving resistance to EGFR-targeted therapies in colorectal cancer.

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