UNIVERSITY OF CALGARY

UNIVERSITY OF CALGARY
Synthetic lethality in NSCLC cells: Interrogating the therapeutic potential of ATM deficiency
by
Anifat Aderinola Elegbede
A THESIS
SUBMITTED TO THE FACULTY OF GRADUATE STUDIES
IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE
DEGREE OF MASTER OF SCIENCE
DEPARTMENT OF MEDICAL SCIENCE
FACULTY OF MEDICINE
CALGARY, ALBERTA
SEPTEMBER, 2014
© Anifat A. Elegbede 2014

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Abstract
Previous work by the Bebb and Lees-Miller labs demonstrated poly(ADP)ribose polymerase
inhibitors (PARPi) induced synthetic lethality in Ataxia telangiectasia mutated (ATM) deficient
cells. My work extended these studies to non-small cell lung cancer (NSCLC). In vitro, ATM
deficient NSCLC cell lines were investigated by assessing DNA damage-induced phosphorylated
target proteins and ionizing radiation (IR) sensitivity using the clonogenic assay. Two cell lines,
H23 and H1395, with reduced ATM expression and impaired ATM dependent signalling were
identified. H23 exhibited the expected increased sensitivity to radiation and PARPi. H1395 on
the other hand displayed IR-induced ATM dependent phosphorylation and behaved like its ATM
competent counterparts by being resistant to the investigative agents. These results suggest that
while ATM deficiency may predict sensitivity to radiation and a novel combination of cisplatin
and PARPi additional unidentified factors modulate this phenotype. These observations require
validation in further studies.

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Acknowledgements
I thank the Almighty God for making this work possible. A special thank you to Dr. D. Gwyn
Bebb under the tutelage of whom I carried out this project, thank you so much for accepting me
and given me the opportunity to practice science. It was quite a challenge but for your word of
encouragement which has kept me going from the beginning to the end; GOD BLESS YOU. To
my supervisory committee members, Drs. Sarah Childs and Susan Lees-Miller; I say a big thank
you. Dr. Lees-Miller, the project would not have been completed without your experience,
guidance and suggestions, I cannot stop thanking you for those prompt feedbacks on my work.
Dr. Childs, I’m really grateful for your keen scientific insights. To members of the Medical
Science department and especially Kiran Pandher, thank you all.
I want to extend my appreciations to my great teachers, Huong Muzik, Chris Williamson, Eiji
Kubota and Lars Petersen, for their technical knowledge and supports. Huong, I will forever
appreciate your patience and kindness. Eiji, I cannot thank you enough for your willingness to
always help out of your busy schedule, even while you are far away in Japan. Lars, I really
appreciate your efforts in making my work look professional and the time spent in reviewing my
write-ups.
To every member in Bebb’s lab, (especially Rachel, Shannon, Rosie, Allison,Will); Morris’s
Lab (especially Dr. Morris D., Qiao, Jason, Chandini); Lees-Miller’s lab; Translational Research
lab in general, (Brant, JB, Cay); Elaine Wilkie and everyone that has contributed positively to
my experience, I cannot name you all, thank you for making this a memorable experience.

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Finally, I want to express my utmost gratitude to my loving family; my husband and children
for their supports and understanding; my parents and siblings for their incessant prayers and
supports, I am really grateful to have you all around me.

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Dedication
To all cancer survivors
including my courageous dad