Journal-Based CME: MYC-mediated Resistance to Trametinib and HCQ in PDAC is Overcome by CDK4/6 and Lysosomal Inhibition

Thursday, January 19, 2023, 3:00 PM - Monday, January 19, 2026, 4:00 PM

This Journal-Based CME activity consists of a full-text article that is free to read, a multiple-choice question test, and an evaluation/self-assessment. Learners are tested on their comprehension of the key concepts, with the objective of enriching their clinical practice and patient care through better understanding of scientific advances and new techniques in the fields covered by Journal of Experimental Medicine (JEM).

Questions for this complimentary, online-only activity have been designed by JEM editors in collaboration with the article authors. Each CME activity should take approximately 1 hour to complete.

The article selected for this activity is MYC-mediated resistance to trametinib and HCQ in PDAC is overcome by CDK4/6 and lysosomal inhibition by Mark Silvis, Dilru Silva, Martin McMahon, Conan Kinsey, and colleagues at the Huntsman Cancer Institute and University of Utah.

Article Abstract

Pharmacological inhibition of KRAS>RAF>MEK>ERK signaling has provided no clinical benefit to patients with pancreatic ductal adenocarcinoma (PDAC). Interestingly, combined inhibition of MEK1/2 (with trametinib [T]) plus autophagy (with chloroquine [CQ] or hydroxychloroquine [HCQ]) demonstrated striking anti-tumor effects in preclinical models and in a patient (Patient 1). However, not all patients respond to the T/HCQ regimen, and Patient 1 eventually developed resistant disease. Here we report that primary or acquired resistance is associated with focal DNA copy number gains encompassing c-MYC. Furthermore, ectopic expression of c-MYC in PDAC cell lines rendered them T/HCQ resistant. Interestingly, a CDK4/6 inhibitor, palbociclib (P), also induced autophagy and overrode c-MYC–mediated T/HCQ resistance, such that P/HCQ promoted regression of T/HCQ-resistant PDAC tumors with elevated c-MYC expression. Finally, P/HCQ treatment of Patient 1 resulted in a biochemical disease response. These data suggest that elevated c-MYC expression is both a marker and a mediator of T/HCQ resistance, which may be overcome by the use of palbociclib plus HCQ.

About Journal of Experimental Medicine (JEM) and CME Activities

JEM publishes peer-reviewed papers within the field of medical biology, providing novel conceptual insights into immunology, cancer biology, neuroscience, inflammation, vascular biology, microbial pathogenesis, and stem cell biology. These studies range from original findings on all aspects of disease pathogenesis to novel therapeutic approaches. Articles designated for Journal-Based CME have been selected by JEM editors for their clinical relevance and ability to address practice-based gaps.

Select the 'Course Content' tab at the top of this page in order to access the full article and claim CME credit.

1. Comprehend key points in the research findings outlined in the activity.
2. Differentiate between old and new concepts.
3. Learners will have the information necessary to apply the relevant points to their clinical practice.

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Memorial Sloan Kettering Cancer Center, the Journal of Experimental Medicine (JEM) and Rockefeller University Press. Memorial Sloan Kettering Cancer Center is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

AMA Credit Designation Statement

Memorial Sloan Kettering Cancer Center designates this enduring material for a maximum 1.00 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

 

Recorded/Review Date: January 19, 2023 | Original Release Date: January 19, 2023 | Termination Date: January 19, 2026

Mitigation of Relevant Financial Relationships

Memorial Sloan Kettering Cancer Center adheres to the ACCME’s Standards for Integrity and Independence in Accredited Continuing Education. Any individuals in a position to control the content of a CE activity, including faculty, planners, reviewers or others are required to disclose all relevant financial relationships with ineligible entities (commercial interests). All relevant conflicts of interest have been mitigated prior to the commencement of the activity.