Abstract C30: Myc amplification is a negative biomarker and a resistance mechanism to trametinib/HCQ treatment, but can be overcome by combined palbociclib/HCQ treatment
Authors: Kinsey Conan , Silva Dilru , Silvis Mark , Schuman Sophia , Affolter Kajsa , McMahon Martin 
Published: March 2020

Pancreatic ductal adenocarcinoma (PDAC) is a recalcitrant disease responsible for ~43,000 deaths in the USA in 2017. Despite an advanced understanding of the genetics, biochemistry, and biology of pancreatic cancer, there is no effective pathway-targeted therapy for PDAC such that the standard-of-care treatment for most patients remains conventional cytotoxic chemotherapy. Although the clinical picture remains grim, progress has been made in understanding how alterations in tumor suppressors and proto-oncogenes contribute to PDAC initiation and progression. Whereas initiating mutations in KRAS promote the growth of premalignant pancreatic intraepithelial neoplasia, progression to cancer malignancy requires cooperating alterations of tumor suppressors such as TP53, CDKN2A, and/or SMAD4. Downstream of KRAS oncoproteins, the RAF®MEK®ERK MAP kinase signaling pathway plays a central role in the genesis of PDAC. However, to date, pharmacologic inhibition of this pathway has demonstrated little clinical benefit in PDAC patients. We have previously shown that combined inhibition of MEK1/2 and autophagy with chloroquine/hydroxychloroquine (CQ/HCQ) displays synergistic antiproliferative effects against PDAC cell lines in vitro, in xenografted patient-derived PDAC tumors, and treatment of a pancreatic cancer patient with trametinib/HCQ resulted in dramatic tumor regression. Unfortunately, this patient did go on to progress on trametinib/HCQ therapy and a second patient who was treated with the combination of trametinib and hydroxychloroquine was refractory to treatment. Strikingly, the only genetic difference between these two patients’ tumors at the start of trametinib/HCQ treatment was an MYC amplification, and our first patient demonstrated an acquired MYC amplification upon development of resistance. Here we demonstrate in preclinical models that overexpression of MYC in Mia-PaCa2 and PDX220 cells lines resulted in both refractory and resistant tumors. We have identified that the CDK4/6 inhibitor, palbociclib, also induces protective autophagy, and treating xenografted Mia-PaCa2 tumors overexpressing MYC with palbociclib/CQ resulted in striking tumor regression. We therefore tested the combination of palbociclib/CQ on PDX derived from our first patient upon resistance to trametinib/HCQ, which demonstrated regression and suppression of tumors when treated with palbociclib/CQ, but not palbociclib alone or trametinib/CQ. Finally, we treated our first patient with the combination of palbociclib/HCQ and saw a dramatic decline in CA19-9. These data suggest that MYC amplification may be a negative biomarker for response and also a resistance mechanism that can be overcome with combined inhibition of CDK4/6 and autophagy.

Citation Format: Conan Kinsey, Dilru Silva, Mark Silvis, Sophia Schuman, Kajsa Affolter, Martin McMahon. Myc amplification is a negative biomarker and a resistance mechanism to trametinib/HCQ treatment, but can be overcome by combined palbociclib/HCQ treatment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C30.