08 Apr Combination Inhibitors May Attack More Lung Cancers
MedicalResearch.com Interview with:
Nada Kalaany, PhD
Harvard Medical School
Boston Children’s Hospital
Boston, MA 02115
MedicalResearch.com: What is the background for this study?
Response: Non-small cell lung cancer (NSCLC) is the predominant form of lung cancer and the leading cause of cancer death in the US and worldwide. Over a quarter of NSCLC harbors activating mutations in the KRAS oncogene, which despite decades of attempts, has proven to be very difficult to target.
KRAS has previously been demonstrated to directly bind to and activate the pro-proliferative kinase PI3K, which is typically activated by insulin/insulin-like growth factor1 (IGF1) signaling. KRAS-PI3K binding is required for KRAS-driven lung cancer formation and progression. However, whether this interaction is sufficient for lung tumor formation and whether additional input is required from insulin/IGF1 signaling, has remained largely controversial.
MedicalResearch.com: What are the main findings?
Response: Our study uses genetic means to robustly address this long-standing question in KRAS-driven lung cancer. We demonstrate that mice with genetic loss of the insulin receptor substrates: Irs1 and Irs2, adaptor proteins that are necessary for insulin/IGF1 signaling, have significantly delayed Kras-driven lung tumor formation, even in the absence of the tumor suppressor p53. Furthermore, these mice survive twice as long as control mice expressing Irs1 and Irs2 genes.
Interestingly, the Irs1/Irs2-null tumors that eventually arise in these mice have strikingly lower levels of essential amino acids, nutrients that need to be taken-up from the diet and constitute the building blocks for the synthesis of proteins. When insulin/IGF1 signaling is suppressed in mouse or human NSCLC cells, either genetically or pharmacologically, the uptake of these essential amino acids is also decreased.
Interestingly, we find that these tumor cells attempt to compensate for such low levels of amino acids, by inducing a “self-eating” process termed “autophagy”, that can provide essential amino acids from the breakdown of proteins.
Indeed, inhibition of autophagy or that of another protein breakdown process mediated by the “proteasome”, significantly mitigates the growth of NSCLC tumors with suppressed insulin/IGF1 signaling.
MedicalResearch.com: What should readers take away from your report?
Response: Insulin/IGF1 signaling is necessary for the formation of KRAS-driven lung cancer.
However, inhibiting insulin/IGF1 signaling alone may not be sufficient to treat KRAS-driven lung cancer; In fact, previous clinical trials using IGF1 receptor (IGF1R) inhibitors have failed. We find that tumor cells exploit other means to compensate for the resulting suppression of amino acid uptake by promoting cellular protein breakdown. This includes autophagy induction and enhanced proteasome activity.
Our study suggests that therapies combining IGF1R inhibitors with inhibitors of autophagy or the proteasome, might constitute a more effective strategy to treat KRAS-driven lung cancer.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: A direct follow-up of our findings is to validate our hypothesis by running clinical trials for KRAS-driven NSCLC, that test combination therapy regimens using available IGF1R inhibitors with either the autophagy inhibitor drug chloroquine (currently in use in several cancer drug trials) or the proteasome inhibitor bortezomib (known as Velcade, currently used to treat multiple myeloma).
MedicalResearch.com: Is there anything else you would like to add?
Response: As in any combination therapy, dosing should be carefully adjusted to avoid toxicities. It would also be ideal if such therapies were targeted specifically to the lungs.
I have no disclosures.
He Xu, Min-Sik Lee, Pei-Yun Tsai, Ashley S. Adler, Natasha L. Curry, Saketh Challa, Elizaveta Freinkman, Daniel S. Hitchcock, Kyle D. Copps, Morris F. White, Roderick T. Bronson, Michael Marcotrigiano, Yaotang Wu, Clary B. Clish, Nada Y. Kalaany. Ablation of insulin receptor substrates 1 and 2 suppressesKras-driven lung tumorigenesis. Proceedings of the National Academy of Sciences, 2018; 201718414 DOI: 10.1073/pnas.1718414115
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