Anita T. Shaffer

A technique involving BH3 profiling is emerging as a promising drug discovery tool for assessing whether a tumor is primed for cell death and would respond to anticancer therapy, according to a presentation at the 2019 Association for Molecular Pathology Annual Meeting and Expo.

Dynamic BH3 profiling, as the technique is called, is an example of an evolving approach to precision medicine in which investigators examine the &ldquo;functional phenotype&rdquo; of a tumor rather than relying on genomic analysis, said Anthony G. Letai, MD, PhD, whose laboratory at the Dana-Farber Cancer Institute has pioneered the concept.

During the development of venetoclax (Venclexta), Letai and colleagues profiled interactions of BH3-only proteins, which are members of the bcl-2 family, as a predictive marker of response to the drug.

In 2016, venetoclax became the first FDA-approved bcl-2 inhibitor; it is now indicated for use in chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma and acute myeloid leukemia (AML) settings.

The rationale for focusing on BH3 stems from the role of bcl-2 proteins in the complex interactions that modulate apoptotic signaling. Apoptosis is regulated at the mitochondrial level and involves interactions among the more than 15 bcl-2 proteins that can be either proapoptotic or antiapoptotic.

Mitochondrial apoptotic priming is the primary reason that chemotherapy works and can &ldquo;assign BH3 mimetics where they belong&rdquo; to promote an anticancer response, Letai, associate professor of medicine at Harvard Medical School in Boston, Massachusetts, said in his presentation. As a result, he said, increases in priming due to therapy can be used to identify targeted therapies that are more likely to be effective.

&ldquo;BH3 profiling is exposing mitochondria to a panel of BH3 peptides and measuring quantitating&mdash;mitochondria permeabilization. That gives us a measure of how primed the mitochondria are for apoptosis,&rdquo; Letai said in an interview with Targeted Therapies in Oncology. &ldquo;In dynamic BH3 profiling, we do that process but we precede it with a drug exposure. Then what we can say is, &lsquo;Did the drug exposure increase the apoptotic priming?&rsquo; We get drug-specific information about that cell.

&ldquo;If we have a cell where we expose it to a drug and we find that its apoptotic priming goes up as measured by dynamic BH3 profiling compared with an untreated [cell], then that means that drug initiated apoptotic signaling in that tumor sample,&rdquo; he added.

In 2007, Letai and colleagues used BH3 profiling to predict sensitivity to a bcl-2 antagonist then under investigation for CLL.

The hypothesis that AML cells also are bcl-2 dependent initially was met with skepticism, but preclinical studies showed that there is a built-in therapeutic index for bcl-2 inhibition in AML, Letai said.

Letai emphasized that BH3 profiling has helped identify a targeted therapy for these malignancies, whereas genomic profiling has not turned up actionable mutations in either cancer type. Because of this, he believes that new dimensions are needed in precision medicine.

&ldquo;The paradigm for precision medicine in oncology is pretty much universally genetics,&rdquo; he said. &ldquo;We need to move beyond omics and static approaches.&rdquo;

Further work by Letai and his team shows that dynamic BH3 profiling can also be effective in solid tumor samples.

Investigators used solid tumor cell lines for breast cancer, nonsmall cell lung cancer, melanoma, and colon cancer to test their hypothesis. They exposed cancer cells to different kinase inhibitors and performed dynamic BH3 profiling. The percentage of cells with an increase in priming was significantly higher for treated cells versus untreated cells at 16 hours of exposure, as was cell death at 96 hours, which investigators said was indicative of the predictive value of dynamic BH3 profiling (area under the curve, 0.96; 95% CI, 0.91-1.02;

Letai&rsquo;s laboratory is developing technology to test multiple drugs on 1 sample, he said. The process involves fresh isolation of primary or patient-derived xenograft tumor cells followed by incubating the cells with different drugs for 24 hours, conducting BH3 profiling with a synthetic peptide, performing high-throughput imaging, quantifying drug-induced priming changes, and identifying the drugs that caused the greatest priming changes.

&ldquo;We can now test thousands of drugs on the same sample as long as we have enough cells to distribute to the different wells,&rdquo; Letai said. &ldquo;We&rsquo;re now at a phase where we can do primary discovery directly on patient primary tissues in addition to smaller clinical diagnostic studies.&rdquo;

Letai said that many investigators are working throughout the world on various dynamic assays. He is president of the Society for Functional Precision Medicine, which seeks to advance the development of such tools. In order to move forward, the field will need the involvement of pathologists, Letai emphasized.

&ldquo;A demand that these types of functional assays make is that we have living, viable tissue,&rdquo; Letai said, which contrasts with current omics testing practices.

&ldquo;The first thing we do when we get tissue out of a patient is we kill it with formalin,&rdquo; Letai said. &ldquo;We have to think twice before we immediately kill the samples that are coming out of patients because as soon as we kill these samples, the ability to gain functional information is lost. This functional information can be incredibly valuable in actually choosing the drugs that are going to work in [patients with] cancer.&rdquo;

Letai A. Choosing patient therapy with dynamic BH3 profiling. Presented at: 2019 Association for Molecular Pathology Annual Meeting; November 7-9, 2019; Baltimore, MD.

Pan R, Hogdal LJ, Benito JM, et al. Selective BCL-2 inhibitor by ABT- 199 causes on-target cell death in acute myeloid leukemia. Cancer Discov. 2013;4(3):362-375. doi: 10.1158/2159-8290.CD-13-0609.

Venclexta [package insert]. North Chicago, IL: AbbVie Inc; 2019. bit. ly/32zwkyb. Accessed November 7, 2019.

BH3 profiling introduction. The Letai Lab. Dana-Farber Cancer Institute website. bit.ly/2Q5sw59. Accessed November 7, 2019.

Del Gaizo Moore V, Brown JR, Certo M, Love TM, Novina CD, Letai A. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest. 2007;117(1):112-121. doi: 10.1172/JCI28281.

Montero J, Sarosiek KA, DeAngelo JD, et al. Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy. Cell. 2015;160(5):977-989. doi: 10.1016/j.cell.2015.01.042.

Articles

Dynamic Tumor Cell Profiling Technique Moves Therapy Beyond Genomics

The emergence of resistance mutations in patients with cancer who receive targeted therapies is an expected development that will require new diagnostic methods of identifying the mechanisms through which these alterations occur, according to Fei Dong, MD.

Large-scale next-generation sequencing (NGS) studies, such as The Cancer Genome Atlas, have resulted in the characterization of most primary targetable oncogenic mutations in common cancer types, Dong said during a presentation at the 2019 Association for Molecular Pathology Annual Meeting.

He finds novel resistance mutations to be an interesting and developing area.

&ldquo;In the last few years within our field we&rsquo;ve seen tremendous change,&rdquo; said Dong, an assistant professor of pathology at Brigham and Women's Hospital in Boston, Massachusetts. &ldquo;Specifically, we&rsquo;ve seen the transition from single-gene tests to NGS-based genotyping and cancer diagnostics. This has led to increased complexity in variant analysis and clinical interpretation.&rdquo;

, Dong said that resistance mutations present new challenges for molecular pathologists. &ldquo;The emergence of resistance mutations means that we have to optimize our assays to detect the new areas within the genes that we were previously testing to identify mutations that are known to be mechanistically important and we have to adjust our assays appropriately as new mechanisms of resistance pop up,&rdquo; he said.

During his presentation, Dong stressed that cancers are characterized by clonal evolution. &ldquo;Cancer is a clonal process, but within a cancer clone there can be genetically defined subclones, and during the process of cancer evolution there can be branch events that represent key events in either cancer progression or metastasis, or when the cancer is exposed to selection pressure, such as exposure to certain types of therapies,&rdquo; he said.

To illustrate that point, Dong discussed 3 areas: resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), lung cancer, and colorectal cancer (CRC); mechanisms that cause resistance to hormone therapy in breast cancer and PARP inhibitor therapy in

-deficient tumors; and emerging evidence of immune evasion in response to immune checkpoint inhibitors (ICIs).

In CML, Dong detailed the development of TKIs that inhibit the BCR-ABL tyrosine kinase, starting with the discovery in 1960 of the Philadelphia chromosome abnormality that causes the alteration. &ldquo;The story of BCR-ABL is really tremendous and it&rsquo;s classic,&rdquo; he said. &ldquo;It&rsquo;s a paradigm within our field about targeted therapies against genetic alterations and it&rsquo;s also a story that spans over 50 years.&rdquo;

Resistance mutations that develop in response to imatinib (Gleevec) therapy, the first drug targeting BCR-ABL to gain FDA approval, were first observed in

in 2002, Dong said. Molecular analyses identified kinase domain mutations, particularly at T315I, as the cause of resistance, and ponatinib (Iclusig) was shown to specifically target the aberration.

In nonsmall cell lung cancer (NSCLC), the correlation between

mutation and gefitinib (Iressa) therapy was first established in 2004, according to Dong. The T790M mutation was subsequently identified as conferring resistance to EGFR inhibitors. Osimertinib (Tagrisso) was approved in 2015  specifically for patients with the T790M mutation who had progressed on prior EGFR TKI therapy; it has since been approved for first-line therapy in those with metastatic NSCLC that harbors

exon 19 deletions or exon 21 L858R mutations.

Before osimertinib gained approval though, investigators had already found acquired resistance mutations to the agent in

C797S by conducting NGS testing on cell-free plasma DNA samples.

fusionpositive NSCLC, multiple resistance mutations have been characterized in patients who receive ALK-targeting TKIs, most frequently in L1196M and G1269A. Investigators found that each ALK inhibitor has a &ldquo;distinct spectrum&rdquo; of resistance mutations; 1 abberation, a mutation in

G1202R, confers high-level resistance to second-generation ALK inhibitors.

In CRC, an analysis of circulating tumor DNA from patients who initially responded to EGFR TKIs showed mutations in

amplification. Investigators also showed that

mutations changed dynamically with treatment, Dong said.

Turning his attention to other types of therapy, Dong pointed out that mutations in the

ligand-binding domain, most commonly in codons 536 to 538 and E380Q, are associated with treatment with aromatase inhibitors (AIs). Nevertheless, patients with

mutations still respond to estrogen receptor therapy, although study findings show that progression-free survival (PFS) is higher for those treated with fulvestrant (Faslodex), a selective estrogen receptor degrader, compared with the AI exemestane (HR, 0.52; 95% CI, 0.30-0.92;

For agents that target DNA repair pathways, Dong noted that secondary

mutations have been implicated in resistance to PARP inhibitors. Although

-mutated tumors are responsive to PARP inhibition in several malignancies, preclinical studies in pancreatic cancer cell lines show that acquired deletion of a frameshift mutation in

In terms of ICI immunotherapies, understanding of mechanisms of resistance is in the early stages, Dong said. In one study, investigators examined paired tumor specimens before and after therapy from patients with NSCLC who developed resistance after receiving a single-agent PD-1 inhibitor or a combination of PD-1 and CTLA-4 ICIs. They found that resistant clones had lost 7 to 18 mutation-associated neoantigens, damaging the T cells&rsquo; ability to recognize the tumor cells.

Overall, Dong said, genomic changes that occur as a result of acquired resistance are more complex types of mutations that are important to identify for selecting therapies for later lines of treatment. &ldquo;The identification of these resistance mutations is not just for academic purposes,&rdquo; he said. &ldquo;The appropriate clinical variant annotations by us can guide the appropriate treatment selections for the patient in terms of secondary and tertiary therapy. As a field, we should anticipate the need for new methods to identify genetic resistance mechanisms.&rdquo;

Dong F. Novel mechanisms of acquired resistance to targeted therapies in cancer. Presented at: 2019 Association for Molecular Pathology Annual Meeting; November 7-9, 2019; Baltimore, MD.

O'Hare T, Shakespeare WC, Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance.

2009;16(5):401-412. doi: 10.1016/j.ccr.2009.09.028.

Tagrisso [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2018. www.accessdata.fda.gov/drugsatfda_docs/label/2018/208065s011lbl.pdf. Accessed November 8, 2019.

Thress KS, Paweletz CP, Felip E, et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M.

. 2015;21(6):560-562. doi: 10.1038/nm.3854.

Gainor JF, Dardaei L, Yoda S, et al. Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer.

2016;6(10):1118-1133. doi: 10.1158/2159-8290.CD-16-0596.

Siravegna G, Mussolin B, Buscarino M, et al. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients [erratum in

2015;21(7):795-801. doi: 10.1038/nm.3870.

Fribbens C, O&rsquo;Leary B, Kilburn L, et al. Plasma ESR1 mutations and the treatment of estrogen-receptor positive advanced breast cancer.

2016;34(25):2961-2968. doi: 10.1200/JCO.2016.67.3061.

Edwards SL, Brough R, Lord CJ, et al. Resistance to therapy caused by intragenic deletion in BRCA2.

. 2008;451(7182):1111-1115. doi: 10.1038/nature06548.

Anagnostou V, Smith KN, Forde PM, et al. Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer.

2017;7(3):264-276. doi: 10.1158/2159-8290.CD-16-0828.

The emergence of resistance mutations in patients with cancer who receive targeted therapies is an expected development that will require new diagnostic methods of identifying the mechanisms through which these alterations occur, according to Fei Dong, MD, during the 2019 Association for Molecular Pathology Annual Meeting.<br />
&nbsp;

Resistance Mutations Pose Complex Challenges for Pathologists

ex14) skipping mutations in patients with nonsmall cell lung cancer (NSCLC) presents a complex diagnostic challenge that requires both DNA and RNA analysis, according to results of a University of Michigan pathology study.

The question of how best to detect this mutation becomes more clinically relevant as therapies are designed for this population, David M. Manthei, MD, PhD, noted in presenting the findings at the Association for Molecular Pathology 2019 Annual Meeting and Expo.

Three tyrosine kinase inhibitors have received breakthrough therapy designations from the FDA for patients with

ex14 aberrations: 2 investigational agents capmatinib and tepotinib, as well as crizotinib (Xalkori), which is approved in

ex14 skipping mutations have been found in 2% to 5% of lung adenocarcinomas, depending on the study, said Manthei, a fellow in the Department of Pathology at Michigan Medicine in Ann Arbor. These alterations have been described as somatic mutations that affect sites of RNA splicing, resulting in the skipping of

Investigators have found that these alterations can occur due to point mutations and deletions that affect splicing or through exon 14 deletion, Manthei said. Alterations can occur between exons 13 and 14 and between exons 14 and 15. When exon 14 is excluded, &ldquo;the tyrosine kinase protein is more stable and can have prolonged kinase signaling, which can lead to the deleterious effect,&rdquo; he said.

After analyzing testing approaches, Manthei and colleagues concluded that a combined DNA and RNA workflow detects

ex14 mutations that would not be identified with DNA-only analysis. They also found that RNA-based methods yield information on variant splicing that might not surface otherwise.

Manthei discussed the advantages and disadvantages of current methods of detecting

ex14 alterations: DNA testing offers a more robust substrate and mutations in exons that are often well defined but coverage depends on the design of the testing panel being used and less common variants may not be described in functional studies.

RNA testing provides information on the functional effect of mutations with coverage of many aberrations in a single assay, but the substrate is more changeable, the analytical process involves additional steps, and alternative splicing makes the results harder to interpret.

The experience with the number of fusions detected in mutation testing led investigators to question assay findings more specifically, Manthei said. The team conducted a retrospective analysis of tissue samples from 482 patients using the Oncomine Focus Assay (OFA),

a next-generation sequencing test designed for clinical research.

ex14 DNA mutations, 7 cases (1.5%) with no alternative drivers were identified. In 61 cases (12.7%), no mutation in

ex14 was detected but 42 of these samples had alternative drivers including

fusions. Fusion reads ranged from 16 to 59 per sample in the mutation group and from 1 to 12 in those without a mutation.

&ldquo;We saw a wide range of fusion reads and no other drivers that were present,&rdquo; Manthei said. &ldquo;However, there were an additional 61 cases that had at least some fusion reads that were present based on the assay. The question is what do you do with them? How do you interpret them?&rdquo;

When there are alternative drivers, &ldquo;it may not make sense to think of it as an underlying

fusion event there,&rdquo; he added.&nbsp;

Although OFA can analyze both materials, its DNA coverage of

ex14 detects mutations in the splice donor site (3&rsquo; end) but not the splice acceptor site (5&rsquo; end), investigators said in their conference poster. For RNA, the assay can detect

exon 13 to 15 fusions, but interpretive thresholds have not been defined.

ex14 mutations with RNA fusions, investigators used OFA and then Sanger sequencing. The Sanger method was used on the 5&rsquo; end of

ex14 on residual DNA for cases in which RNA suggested a skipping mutation, defined as the percentage of

ex14 fusion (%fusion) reads &ge;0.03% (0.05% from lowest confirmed case).

Overall, investigators identified 11 cases (2.3%) with

ex14 mutations: 8 with 3&rsquo; end alterations by OFA sequencing and 3 with 5&rsquo; end aberrations by Sanger. Ten of the 11 cases had adequate RNA reads by OFA; those samples demonstrated %fusion reads ranging from 0.082 to 22.1 and %fusion reads per

Additionally, 58 cases with RNA fusion reads by OFA analysis that did not have detectable

ex14 DNA mutations, which investigators said could indicate alternative splicing.

The combined approach offers a better picture of the

ex14 landscape, according to Manthei. &ldquo;The OFA assay is picking up what it&rsquo;s supposed to and we&rsquo;re also able to now interrogate whether additional DNA mutations might be underlying these fusion readings,&rdquo; he said.

Nevertheless, Manthei said, some fusion reads still have no clear answer. In such instances, &ldquo;we might want to be [reflexively sending a borderline case] to something like Sanger sequencing to really inform whether a mutation is present or not,&rdquo; he said.

Although the use of RNA-based methods improves the analysis, Manthei said, caution is needed in interpreting the results: RNA fusion reads can be detected in nonmutated samples, and determining a threshold for true positivity is challenging. The specificity of the threshold can be improved significantly by normalizing the analysis to total RNA reads and

Manthei D, Weigelin H, Kleyman-Smith Y, Brown N, Betz B. Improved detection of MET exon 14 skipping mutations in lung adenocarcinoma with combined DNA/RNA testing and refined analysis methods. Poster presented at: 2019 Association for Molecular Pathology Annual Meeting and Expo; November 7-9, 2019; Baltimore, MD. Poster ST-009.

Breakthrough therapies. Friends of Cancer Research website. bit.ly/2X4fyWx. Accessed November 10, 2019.

Frampton GM, Ali SM, Rosenzweig M, et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors.

. 2015;5(8):850-859. doi: 10.1158/2159-8290.CD-15-0285.

Oncomine Focus Assay. ThermoFisher Scientific website. bit.ly/33MxY0s. Accessed November 10, 2019.

The identification of&nbsp;<em>MET&nbsp;</em>exon 14 skipping mutations in patients with non&ndash;small cell lung cancer presents a complex diagnostic challenge that requires both DNA and RNA analysis, according to results of a University of Michigan pathology study.

Study Depicts Complexity of MET Exon 14 Mutation Testing

A technique involving BH3 profiling is emerging as a promising drug discovery tool for assessing whether a tumor is primed for cell death and would respond to anticancer therapy, according to a presentation at the 2019 Association for Molecular Pathology Annual Meeting.

Dynamic BH3 profiling, as the technique is called, is an example of an evolving approach in precision medicine in which investigators examine the &ldquo;functional phenotype&rdquo; of a tumor rather than relying upon genomic analysis, said Anthony G. Letai, MD, PhD, whose laboratory at the Dana-Farber Cancer Institute has pioneered the concept.

Letai and colleagues profiled interactions of BH3-only proteins, which are members of the BCL-2 family, as a predictive marker of response to venetoclax (Venclexta) during the drug&rsquo;s development process.

In 2016, venetoclax became the first FDA-approved BCL-2 inhibitor; it is now indicated in chronic lymphocytic leukemia (CLL), small lymphocytic leukemia, and acute myeloid leukemia settings.

The rationale for focusing on BH3 stems from the role of BCL-2 proteins in the complex interactions that modulate apoptotic signaling, which is regulated at the mitochondria level.

The process involves interactions among the more than 15 members of the BCL-2 proteins that can be either proapoptotic or antiapoptotic.

Mitochondrial apoptotic priming is the primary reason that chemotherapy works and can &ldquo;assign BH3 mimetics where they belong&rdquo; to promote an anticancer response, Letai said in his presentation. As a result, he said, measuring increases in priming due to therapy can be used to identify targeted therapies more likely to be effective.

&ldquo;BH3 profiling is exposing mitochondria to a panel of BH3 peptides and measuringquantitating&mdash; mitochondria permeabilization. That gives us a measure of how primed the mitochondria are for apoptosis,&rdquo; Letai said in an interview with

. &ldquo;In dynamic BH3 profiling, we do that process but we precede it with a drug exposure. Then what we can say is, did the drug exposure increase the apoptotic priming? We get drug-specific information about that cell.

In 2007, Letai and colleagues used BH3 profiling to predict sensitivity to a BCL-2 antagonist then under investigation for CLL.

The hypothesis that AML cells also are BCL-2 dependent initially was met with skepticism but preclinical studies showed that there is a built-in therapeutic index for BCL-2 inhibition in AML, Letai said.

Letai emphasized that BH3 profiling has helped identify a targeted therapy for these malignancies, whereas genomic profiling has not indicated any mutations that would have suggested the use of BCL-2 inhibitors in these cancers. He said that supports his contention that new dimensions are needed in precision medicine.

Further work by his team shows that dynamic BH3 profiling can also be effective in solid tumor samples. Investigators used solid tumor cell lines for breast cancer, nonsmall cell lung cancer, melanoma, and colon cancer to test their hypothesis. The cells were exposed to different kinase inhibitors and dynamic BH3 profiling was performed. The percentage of cells with an increase in priming was significantly higher for treated cells versus untreated cells at 16 hours of exposure, as was cell death at 96 hours, which investigators said was indicative of the predictive value of dynamic BH3 profiling (area under the curve, 0.96; 95% CI, 0.91-1.02;

The technology to test multiple drugs on 1 sample is being developed in his laboratory, he said. The process involves fresh isolation of primary or patient-derived xenograft tumor cells, incubating the cells with different drugs for 24 hours, conducting BH3 profiling with a synthetic peptide, performing high-throughput imaging, quantifying drug-induced priming changes, and identifying the drugs that caused the greatest priming changes.

&ldquo;We can now test thousands of drugs on the same sample as long as we have enough cells to distribute to the different wells of the drug,&rdquo; Letai said. &ldquo;We&rsquo;re now at a phase where we can do primary discovery directly on patient primary tissues in addition to smaller clinical diagnostic studies.&rdquo;

Letai said many investigators are working throughout the world on various dynamic assays. He is president of the Society for Functional Precision Medicine, which seeks to advance the development of such tools. In order to move forward, the field will need the involvement of pathologists, Letai emphasized.

&ldquo;A demand that these types of functional assays make is that we have living, viable tissue,&rdquo; which contrasts with current omics testing practices, he said.

&ldquo;The first thing we do when we get tissue out of a patient is we kill it with formalin,&rdquo; Letai said. &ldquo;&hellip;We have to think twice before we immediately kill the samples that are coming out of patients because as soon as we kill these samples, the ability to gain functional information is lost. This functional information can be incredibly valuable in actually choosing the drugs that are going to work in [patients with] cancer.&rdquo;

Pan R, Hogdal LJ, Benito JM, et al. Selective BCL-2 inhibitor by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov. 2013;4(3);362-375. doi: 10.1158/2159-8290.CD-13-0609.

Venclexta [prescribing information]. North Chicago, IL: AbbVie Inc; 2019. www.accessdata.fda.gov/drugsatfda_docs/label/2019/208573s011s014s015lbl.pdf. Accessed November 7, 2019.

The Letai Lab. BH3 profiling introduction. Dana-Farber cancer Institute website. letailab.dana-farber.org/bh3-profiling.html. Accessed November 7, 2019.

Del Gaizo Moore V, Brown JR, Certo M, Love TM, Novina CD, Letai A. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737.

2007;117(1):112-121. doi: 10.1172/JCI28281.

Montero J, Sarosiek KA, DeAngelo JD, et al. Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy.

2015;160(5):977-989. doi: 10.1016/j.cell.2015.01.042.

Author | Anita T. Shaffer

Articles

Dynamic Tumor Cell Profiling Technique Moves Therapy Beyond Genomics

Resistance Mutations Pose Complex Challenges for Pathologists

Study Depicts Complexity of MET Exon 14 Mutation Testing

Dynamic Tumor Cell Profiling Technique Correlates With Therapy Responses