Trametinib and Hydroxychloroquine (HCQ) Combination Treatment in KRAS-Mutated Advanced Pancreatic Adenocarcinoma: Detailed Description of Two Cases

J Gastrointest Cancer. 2021 Mar;52(1):374-380. doi: 10.1007/s12029-020-00556-z. Epub 2020 Nov 23.

Abstract

Purpose: Over the last decades, cytotoxic chemotherapy has been the cornerstone of metastatic pancreatic adenocarcinoma treatment. In late-stage disease, a range of treatment regimens still offers minor benefits. Molecular profiling studies have shown that pancreatic adenocarcinoma (PDAC) is a mutation-driven tumor type, with KRAS mutations found in approximately 90% of cases, which could partially explain the resistance to chemotherapy. Preclinical data on selective targeting of a downstream point of the RAF-MEK-ERK pathway with a MEK inhibitor along with the concurrent use of an autophagy inhibitor such as hydroxychloroquine appears to be one alternative approach to overcome resistance and inhibit cell proliferation.

Methods: We herein aim to investigate the rationale of autophagy inhibitors use and describe the outcomes of patients who received this experimental treatment.

Results: Two patients have received this experimental regimen from January 2020 to the present date, achieving disease stabilization that is clinically meaningful, considering the chemoresistance scenario of the included patients.

Conclusions: Our real-life data regarding KRAS-mutated PDAC patients who received treatment with the MEK inhibitor trametinib combined with hydroxychloroquine after experiencing disease progression are consistent with the preclinical data, pointing to the clinical benefits of this regimen.

Keywords: Autophagy; Hydroxychloroquine; KRAS protein; Pancreatic cancer.

Publication types

  • Case Reports

MeSH terms

  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Autophagy / drug effects
  • Autophagy / genetics
  • CA-19-9 Antigen / blood
  • Carcinoma, Pancreatic Ductal / diagnosis
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / secondary
  • Disease Progression
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Humans
  • Hydroxychloroquine / pharmacology*
  • Hydroxychloroquine / therapeutic use*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / genetics
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm Staging
  • Pancreas / diagnostic imaging
  • Pancreas / pathology
  • Pancreatic Neoplasms / diagnosis
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology
  • Positron Emission Tomography Computed Tomography
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Pyridones / pharmacology
  • Pyridones / therapeutic use*
  • Pyrimidinones / pharmacology
  • Pyrimidinones / therapeutic use*
  • Treatment Outcome

Substances

  • CA-19-9 Antigen
  • KRAS protein, human
  • Pyridones
  • Pyrimidinones
  • trametinib
  • Hydroxychloroquine
  • Proto-Oncogene Proteins p21(ras)