A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer

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From: Nature Medicine(Vol. 18, Issue 4)
Publisher: Nature Publishing Group
Document Type: Report
Length: 9,221 words
Lexile Measure: 1540L

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Tyrosine kinase inhibitors (TKIs) elicit high response rates among individuals with kinase-driven malignancies, including chronic myeloid leukemia (CML) and epidermal growth factor receptor-mutated non-small-cell lung cancer (EGFR NSCLC). However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual's response to TKIs. Using paired-end DNA sequencing, we discovered a common intronic deletion polymorphism in the gene encoding BCL2-like 11 (BIM). BIM is a pro-apoptotic member of the B-cell CLL/lymphoma 2 (BCL2) family of proteins, and its upregulation is required for TKIs to induce apoptosis in kinase-driven cancers. The polymorphism switched BIM splicing from exon 4 to exon 3, which resulted in expression of BIM isoforms lacking the pro-apoptotic BCL2-homology domain 3 (BH3). The polymorphism was sufficient to confer intrinsic TKI resistance in CML and EGFR NSCLC cell lines, but this resistance could be overcome with BH3-mimetic drugs. Notably, individuals with CML and EGFR NSCLC harboring the polymorphism experienced significantly inferior responses to TKIs than did individuals without the polymorphism (P = 0.02 for CML and P = 0.027 for EGFR NSCLC). Our results offer an explanation for the heterogeneity of TKI responses across individuals and suggest the possibility of personalizing therapy with BH3 mimetics to overcome BIM-polymorphism-associated TKI resistance.

The use of TKIs has elicited remarkable therapeutic responses in individuals presenting with a broad range of malignancies driven by oncogenic kinases (1). However, before the use of TKIs, such malignancies were regarded as highly chemoresistant, as exemplified by breakpoint cluster region (BCR)-c-abl oncogene 1, non-receptor tyrosine kinase (ABL1) kinase-driven CML and EGFR NSCLC (2), (3). After the advent of TKIs, treatment responses in both of these cancers typically approached 80% (refs. 4,5). These clinical observations emphasized the importance of classifying tumors according to their molecular drivers and at the same time stimulated the search for biomarkers that could identify the 20% of individuals at risk for primary or intrinsic TKI resistance, as well as guide therapy to overcome this resistance. In this respect, we note that although polymorphisms in genes regulating drug metabolism provide useful information to modify the dosing of therapeutic agents (6), few examples exist in the germline that predict response to targeted therapies.

Accordingly, we investigated whether polymorphisms affecting TKI sensitivity might account for the 20% of TKI-treated individuals with poor responses and whether these polymorphisms might be enriched among genes that are crucial in the apoptotic response to TKIs. One such candidate gene is BCL2L11 (also known as BIM), which encodes a BH3-only protein that is a BCL2 family member. The BH3-only proteins activate cell death by either opposing the prosurvival members of the BCL2 family (BCL2, BCL2-like 1 (BCL-XL, also known as BCL2L1), myeloid cell leukemia sequence 1 (MCL1) and BCL2-related protein A1 (BCL2A1)) or by binding to the pro-apoptotic BCL2 family members (BCL2-associated X protein (BAX) and BCL2-antagonist/killer 1 (BAK1)) and directly activating their pro-apoptotic functions7. Others have previously shown that several kinase-driven cancers, including CML and EGFR NSCLC, maintain a survival advantage by suppressing BIM...

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Gale Document Number: GALE|A287113130