Posted November 17, 2017
Jeffrey Engelman, M.D., Ph.D., Novartis, formerly at Massachusetts General Hospital
Lecia Sequist, M.D., M.P.H., Massachusetts General Hospital

Targeted therapies are a highly effective and popular approach to treating the lung cancers for which they are available. Unfortunately, these therapies are typically effective only in select patients and for a brief duration, after which the cancer cells develop resistance and the patients no longer respond to therapy. While investigating a protein biomarker that is capable of predicting which cancers are likely to respond to targeted therapies and affect treatment response, Drs. Engelman and Sequist developed two distinct conceptual models by which cancers develop resistance and confirmed that the mechanism of resistance impacts treatment susceptibility.

Drs. Engelman and Sequist received a Fiscal Year 2012 Lung Cancer Research Program Translational Research Partnership Award, with the goals of investigating (1) whether expression of a pro-apoptotic (cell death) protein, BIM, corresponds to a given lung cancer's likelihood of responding to treatment; (2) whether modulations in BIM expression correspond to the development of resistance; and (3) whether therapeutics that increase apoptosis are able to restore the treatment response to cells that have developed resistance. During this study, their laboratories discovered that tumors develop resistance to treatment via one of two mechanisms. In the first model of resistance development, referred to as the �pre-existing model,� a subset of tumor cells has a mutation that is resistant to treatment prior to the first drug exposure. As treatment progresses, the susceptible cells die, but the resistant cells survive until they make up the entirety of the remaining tumor(s). In the second model, referred to as the �persister-evolution model,� a small group of cells in the original tumor are resistant to apoptosis (as evidenced by low-BIM expression). As therapy progresses, these �drug-tolerant� cells develop mutations that impart specific resistance to the targeted therapy.

This discovery is important because it suggests that resistance developed via the second model could possibly be treated and prevented before the genetic mechanisms of resistance develop. By identifying patients with cells that exhibit suppression of the apoptotic response (low-BIM cells) and treating these cells with therapeutics to stimulate apoptosis, it is possible to re-sensitize these cancers to the original targeted therapy. The success of this approach has led to the launch of a clinical trial combining an apoptotic stimulator with targeted therapy in patients demonstrating acquired resistance (NCT02520778).

Dr. Engelman's and Dr. Sequist's success in confirming BIM as a marker for developed resistance to targeted therapy, elucidating the mechanisms by which cancer cells develop resistance, and translating this knowledge to new therapeutic approaches to restore sensitivity is particularly exciting. These findings are paying off for patients who are currently suffering from acquired resistance and are now enrolling in the above-mentioned clinical trial. By combining a targeted therapy with an apoptotic stimulator that targets a key resistance mechanism, it may be possible to improve the success of an otherwise effective, but short-lived, treatment.

Publication:

Hata AN, Niederst MJ, Archibald HL, et al. 2016. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat Med. 22(3):262-269.

Links:

Public and Technical Abstracts: Deficient BIM Expression as a Mechanism of Intrinsic and Acquired Resistance to Targeted Therapies in EGFR-Mutant and ALK-Positive Lung Cancers

Public and Technical Abstracts: Deficient BIM Expression as a Mechanism of Intrinsic and Acquired Resistance to Targeted Therapies in EGFR-Mutant and ALK-Positive Lung Cancers

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