A Barbara Ann Karmanos Cancer Institute and Wayne State University (WSU) research scientist, Husain Yar Khan, Ph.D., presented an abstract on “Targeting XPO1 to Enhance Durability of Response of MRTX1133 in Pancreatic Ductal Adenocarcinoma” at this year’s American Association for Cancer Research (AACR) Annual Meeting in Chicago. The study reviews how to improve the durability of response to KRAS inhibitors by combining them with the XPO1 inhibitor.
In addition, Dr. Khan was awarded the AACR-Ludwig Institute for Cancer Research Scholar-in-Training Award for the study. The Scholar-in-Training Awards at AACR “recognize outstanding young investigators presenting meritorious proffered papers” during the conference.
“I am truly honored to receive the AACR Scholar-in-Training Award. This recognition validates the hard work and dedication I’ve put into my research and motivates me to continue pushing the boundaries of cancer science,” shared Dr. Khan. “This is an opportunity to share my work with the broader scientific community and to learn from some of the leading experts in the field. I sincerely acknowledge Professor Azmi for his exceptional mentorship and critical guidance, which has been pivotal in shaping and advancing this study.”
Pancreatic cancer is one of the deadliest cancers. MRTX1133 is a KRASG12D inhibitor that targets the KRAS mutation, common in pancreatic cancer cases, in the off-state. Investigators know that this inhibitor currently provides limited improvements in disease-free survival, so there is a need to enhance the efficacy of KRAS inhibitors for pancreatic ductal adenocarcinoma.
Dr. Khan is supervised by Asfar Azmi, Ph.D., member of the Molecular Therapeutics Research Program, director of pancreatic cancer research, and associate professor of oncology at WSU School of Medicine.
“Pancreatic cancer is so deadly because the tumor and the microenvironment work collectively to maintain growth and promote drug resistance, meaning most patients experience disease progression,” explained Dr. Azmi. “More than 50% of cancers have the KRAS mutation. In my lab, we focus our research on this mutation and trying to find solutions to curb drug resistance when treating pancreatic cancer.”
The study demonstrates that targeting the nuclear transport protein XPO1 with KPT8602 (an XPO1 inhibitor) can resensitize MRTX1133-resistant pancreatic ductal adenocarcinoma cells and synergistically enhance the antitumor efficacy of MRTX1133 in several preclinical models of pancreatic cancer. This combination improves outcomes and helps delay or prevent resistance.
This is the first study to show that KPT8602 treatment can overcome resistance to MRTX1133 while increasing its effects on pancreatic ductal adenocarcinoma.
“Building on these promising results, our future work will focus on further explaining the mechanisms underlying the interaction between XPO1 and KRASG12D inhibition, identifying biomarkers of response, and optimizing dosing strategies to maximize clinical benefit. We also plan to advance this combination toward clinical evaluation in pancreatic cancer patients, intending to develop more effective, durable treatment options for this aggressive disease,” added Dr. Khan.
Dr. Khan was honored at a reception during the Annual Meeting with other Scholar-in-Training recipients. He also met a representative from the Ludwig Institute for Cancer Research, which sponsored his award. The organization sponsored eight investigators this year.