LMP student seminars: 18 February

Each week during term time, MSc and PhD candidates in the Department of Laboratory Medicine and Pathobiology present their research.

Anyone is welcome. No need to register.

Location: Medical Sciences Building, rooms 4171 or 4279, see below.

As part of the core research curriculum, students taking LMP1001/2/3: Graduate Seminars in Laboratory Medicine and Pathobiology will present their projects. Please see abstracts below.

Group 2: Cancer, Development and Aging

Location: MSB 4171

Mutian Wang

• Title: Turning Resistance Into Opportunity in KRAS-Driven Lung Cancer
• Supervisor: Dr. Ming-Sound Tsao

Group 3: Cardiovascular, Physiology and Metabolism

Location: MSB 4279

Yuejia Yin

• Title: TBA
• Supervisor: TBA

Abstracts

Mutian Wang: Turning Resistance Into Opportunity in KRAS-Driven Lung Cancer

Lung cancer remains the leading cause of cancer-related mortality in Canada. Approximately 13% of lung cancers harbour the driver mutation KRAS G12C. Although sotorasib, a KRAS G12C-specific inhibitor, has been approved in Canada, it elicits clinical responses in only ~37% of patients; the remaining ~60% exhibit intrinsic resistance through largely unknown mechanisms. Exploiting synthetic lethality, whereby simultaneous inhibition of two targets is lethal while inhibition of either target alone is not, may enable combination therapies to overcome this resistance.

Four patient-derived KRAS G12C organoid models exhibiting intrinsic resistance were treated with or without 1 µM sotorasib and screened against the Ontario Institute for Cancer Research kinase inhibitor and toolkit libraries. Hits were defined as genes whose co-inhibition with KRAS reduced cell viability to below 30%, while single-gene inhibition maintained viability above 50%. Across all models, MCL-1 emerged as a prominent target, as combined KRAS and MCL-1 inhibition produced significant synergistic cytotoxicity, whereas single-agent inhibition of either target had a negligible effect.

MCL-1 is an anti-apoptotic protein that is part of the BCL2 family and is commonly upregulated in patients with lung cancer. Knocking down MCL-1 using siRNA restored sensitivity to sotorasib in these models, confirming its role in resistance. Together, this work provides insight into targetable vulnerabilities that may be exploited to overcome KRAS inhibitor resistance in KRAS-driven lung cancer.

Yuejia Yin: TBA

TBA

Contact

No need to register.

Contact lmp.grad@utoronto.ca with any questions.