Mix of lapatinib and a SFK inhibitor partially blocked PI3K activation in the resistant cells and restored sensitivity to lapatinib in BT474 xenografts.95 There also appears to be a role for Src activity in resistance to trastuzumab. cell autonomous experiments and/or loss of function of PTEN. D. Signaling through bypass pathways (e.g., emanating from MET, IGF-1R, EphA2, or EpoR) participate the downstream effectors of HER2 such as PI3K-Akt either directly or through intracellular kinases such as Src. II. INTRINSIC HER2 ALTERATIONS A mechanism of resistance to inhibitors of HER2 is usually mutation of the target itself, resulting in alteration of drug binding. This mechanism is exemplified by the acquired so-called gatekeeper kinase domain name mutations observed in patients with lung malignancy treated with EGFR TKIs and patients with CML and gastrointestinal stromal tumors treated with imatinib.27C32 For HER2, this would also include mutations in the juxtamembrane region that contains the binding epitope of trastuzumab. Anido et al. explained p95-HER2, a truncated form of HER2 lacking the antibody binding region, which arises from alternate transcription initiation sites in HER2.33 This form of HER2 retains kinase activity and is susceptible to inhibition by lapatinib but not trastuzumab.34 Patients with metastatic breast malignancy harboring cytosolic expression of p95-HER2 exhibit a very low response rate to treatment with trastuzumab and chemotherapy compared to those patients without p95-HER2 in their tumors. Conversely, tumors with p95-HER2 are still susceptible to kinase inhibition with a TKI, as was suggested by a similar response rate to capecitabine and lapatinib observed in patients with breast malignancy with and without p95-HER2.35 A recent study reported a nuclear localized truncated form of HER2, also 95 kDa in size, which retains phosphorylation and nuclear localization upon treatment with lapatinib.36 The frequency and clinical significance of this finding are unknown at this time. A splice variant that eliminates exon 16 in the extracellular domain name of the HER2 receptor has also been recognized in HER2+ breast cancers and cell lines.37,38 Cell lines expressing this D16 HER2 isoform are resistant to trastuzumab.38,39 This variant does not eliminate the trastuzumab epitope on HER2, but does appear to stabilize HER2 homodimers and may potentially prevent their disruption upon binding by the antibody.38 In addition, the D16 isoform was found to interact directly with the Src tyrosine kinase, and MLN4924 (Pevonedistat) treatment with MLN4924 (Pevonedistat) the Src inhibitor dasatinib overcame the resistance to trastuzumab conferred by the alternative splicing variant.39 A role for Src kinases in HER2 inhibitor resistance will be further discussed below. Point mutations or small insertions in the HER2 gene have been identified in other cancers. A small number (2%C4%) of non-small-cell lung cancers (NSCLC), as well as gastric, colorectal, and head and neck cancers, have been found to have alterations in the HER2 gene.40C46 These include primarily amino acid substitutions or insertions localized in the kinase domain name. An insertion in exon 20, originally identified in NSCLC, was able to confer resistance to lapatinib and trastuzumab when expressed in breast malignancy cell lines.47 HER2 mutations have been reported in a small number of human breast cancers but in the absence of HER2 gene amplification.41 To our knowledge, HER2 mutations in HER2-overexpressing MLN4924 (Pevonedistat) breast tumors have not been reported to date. One possible reason is usually that these mutations may comprise only a portion of the amplified HER2 alleles and, therefore, exist below the limits of sensitivity of traditional DNA sequencing methods. Nonetheless, using a next-generation sequencing approach with higher sensitivity that was measured to detect a variant frequency as low as 0.08%, no mutations in HER2+ breast cell lines or tumors.Zhuang G, Brantley-Sieders DM, Vaught D, Yu J, Xie L, Wells S, Jackson D, Muraoka-Cook R, Arteaga C, Chen J. overcoming or preventing resistance. than does lapatinib, was shown to induce apoptosis in main HER2+ tumors,22 suggesting the antibody effect may involve a host-antibody conversation not detectable in tumor cell autonomous experiments and/or loss of function of PTEN. D. Signaling through bypass pathways (e.g., emanating from MET, IGF-1R, EphA2, or EpoR) participate the downstream effectors of HER2 such as PI3K-Akt either directly or through intracellular kinases such as Src. II. INTRINSIC HER2 ALTERATIONS A mechanism of resistance to inhibitors of HER2 is usually mutation of the target itself, resulting in alteration of drug binding. This mechanism is exemplified by the acquired so-called gatekeeper kinase domain mutations observed in patients with lung cancer treated with EGFR TKIs and patients with CML and gastrointestinal stromal tumors treated with imatinib.27C32 For HER2, this would also include mutations in the juxtamembrane region that contains the binding epitope of trastuzumab. Anido et al. described p95-HER2, a truncated form of HER2 lacking the antibody binding region, which arises from alternate transcription initiation sites in HER2.33 This form of HER2 retains kinase activity and is susceptible to inhibition by lapatinib but not trastuzumab.34 Patients with metastatic breast cancer harboring cytosolic expression of p95-HER2 exhibit a very low response rate to treatment with trastuzumab and chemotherapy compared to those patients without p95-HER2 in their tumors. Conversely, tumors with p95-HER2 are still susceptible to kinase inhibition with a TKI, as was suggested by a similar response rate to capecitabine and lapatinib observed in patients with breast cancer with and without p95-HER2.35 A recent study reported a nuclear localized truncated form of HER2, also 95 kDa in size, which retains phosphorylation and nuclear localization upon treatment with lapatinib.36 The frequency and clinical significance of this finding are unknown at this time. A splice variant that eliminates exon 16 in the extracellular domain of the HER2 receptor has also been identified in HER2+ breast cancers and cell lines.37,38 Cell lines expressing this D16 HER2 isoform are resistant to trastuzumab.38,39 This variant does not eliminate the trastuzumab epitope on HER2, but does appear to stabilize HER2 homodimers and may potentially prevent their disruption upon binding by the antibody.38 In addition, the D16 isoform was found to interact directly with the Src tyrosine kinase, and treatment with the Src inhibitor dasatinib overcame the resistance to trastuzumab conferred by the alternative splicing variant.39 A role for Src kinases in HER2 inhibitor resistance will be further discussed below. Point mutations or small insertions in the HER2 gene have been identified in other cancers. A small number (2%C4%) of non-small-cell lung cancers (NSCLC), as well as gastric, colorectal, and head and neck cancers, have been found to have alterations in the HER2 gene.40C46 These include primarily amino acid substitutions or insertions localized in the kinase domain. An insertion in exon 20, originally identified in NSCLC, was able to confer resistance to lapatinib and trastuzumab when expressed in breast cancer cell lines.47 HER2 mutations have been reported in a small number of human breast cancers but in the absence of HER2 gene amplification.41 To our knowledge, HER2 mutations in HER2-overexpressing breast tumors have not been reported to date. One possible reason is that these mutations may comprise only a portion of the amplified HER2 alleles and, therefore, exist below the limits of sensitivity of traditional DNA sequencing methods. Nonetheless, using a next-generation sequencing approach with higher sensitivity that was measured to detect a variant frequency as low as 0.08%, no mutations in HER2+ breast cell lines or tumors were detected.48 Another possibility is that these mutations may be selected for or acquired only after the selective pressure of anti-HER2 treatment. If so, they are likely to be detected in tumors that are progressing after primary HER2-targeted therapy. Finally, unique for the case of trastuzumab is the possibility of abrogating drug binding to the target by coexpression of another protein that binds to the drug target. For example, mucin-4 (MUC4), a membrane-associated glycoprotein, when overexpressed can co-localize with HER2 and mask the binding site for trastuzumab.49,50 A cleaved form of another mucin family member, MUC1*, was also found to be overexpressed in a cell line selected for trastuzumab resistance.51 While this cleaved MUC1 isoform has been shown to associate with HER2, and the interaction is enhanced by ligands,52.Spector NL, Xia W, Burris H, Hurwitz H, Dees EC, Dowlati A, ONeil B, Overmoyer B, Marcom PK, Blackwell KL, Smith DA, Koch KM, Stead A, Mangum S, Ellis MJ, Liu L, Man AK, Bremer TM, Harris J, Bacus S. mechanisms of cell cycle regulation or apoptosis, and host factors that may modulate drug response. Emerging clinical evidence already suggests that combinations of therapies targeting HER2 as well as these resistance pathways will be effective in overcoming or preventing resistance. than does lapatinib, was shown to induce apoptosis in primary HER2+ tumors,22 suggesting the antibody effect may involve a host-antibody interaction not detectable in tumor cell autonomous experiments and/or loss of function of PTEN. D. Signaling through bypass pathways (e.g., emanating from MET, IGF-1R, EphA2, or EpoR) engage the downstream effectors of HER2 such as PI3K-Akt either directly or through intracellular kinases such as Src. II. INTRINSIC HER2 ALTERATIONS A mechanism of resistance to inhibitors of HER2 is mutation of the target itself, resulting in alteration of drug binding. This mechanism is exemplified by the acquired so-called gatekeeper kinase domain mutations observed in patients with lung cancer treated with EGFR TKIs and patients with CML and gastrointestinal stromal tumors treated with imatinib.27C32 For HER2, this would also include mutations in the juxtamembrane region that contains the binding epitope of trastuzumab. Anido et al. described p95-HER2, a truncated form of HER2 lacking the antibody binding region, which arises from alternate transcription initiation sites in HER2.33 This form of HER2 retains kinase activity and is susceptible to inhibition by lapatinib but not trastuzumab.34 Individuals with metastatic breast tumor harboring cytosolic expression of p95-HER2 show a very low response rate to treatment with trastuzumab and chemotherapy compared to those individuals without p95-HER2 in their tumors. Conversely, tumors with p95-HER2 are still susceptible to kinase inhibition having a TKI, as was suggested by a similar response rate to capecitabine and lapatinib observed in individuals with breast tumor with and without p95-HER2.35 A recent study reported a nuclear localized truncated form of HER2, also 95 kDa in size, which retains phosphorylation and nuclear localization upon treatment with lapatinib.36 The frequency and clinical significance of this finding are unknown at this time. A splice variant that eliminates exon 16 in the extracellular website of the HER2 receptor has also been recognized in HER2+ breast cancers and cell lines.37,38 Cell lines expressing this D16 HER2 isoform are resistant to trastuzumab.38,39 This variant does not eliminate the trastuzumab epitope on HER2, but does appear to stabilize HER2 homodimers and may potentially prevent their disruption upon binding from the antibody.38 In addition, the D16 isoform was found to interact directly with the Src tyrosine kinase, and treatment with the Src inhibitor dasatinib overcame the resistance to trastuzumab conferred by the alternative splicing variant.39 A role for Src kinases in HER2 inhibitor resistance will be further discussed below. Point mutations or small insertions in the HER2 gene have been identified in additional cancers. A small quantity (2%C4%) of non-small-cell lung cancers (NSCLC), as well as gastric, colorectal, and head and neck cancers, have been found to have alterations in the HER2 gene.40C46 These include primarily amino acid substitutions or insertions localized in the kinase website. An insertion in exon 20, originally recognized in NSCLC, was able to confer resistance to lapatinib and trastuzumab when indicated in breast tumor cell lines.47 HER2 mutations have been reported in a small number of human being breast cancers but in the absence of HER2 gene amplification.41 To our knowledge, HER2 mutations in HER2-overexpressing breast tumors have not been reported to date. One possible reason is that these mutations may comprise only a portion of the amplified HER2 alleles and, consequently, exist below the limits of level of sensitivity of traditional DNA sequencing methods. Nonetheless, using a next-generation sequencing approach with higher level of sensitivity that was measured to detect a variant rate of recurrence as low as 0.08%, no mutations in HER2+ breast cell lines or tumors were recognized.48 Another probability is that these mutations may be selected for or acquired only after the selective pressure of anti-HER2 treatment. If so, they are likely to be recognized in tumors that are progressing after main HER2-targeted therapy. Finally, unique for the case.Cancer Res. coexpression or acquisition of bypass signaling through additional receptor or intracellular signaling pathways, problems in mechanisms of cell cycle rules or apoptosis, and host factors that may modulate drug response. Emerging medical evidence already suggests that mixtures of therapies focusing on HER2 as well as these resistance pathways will be effective in overcoming or preventing resistance. than does lapatinib, was shown to induce apoptosis in main HER2+ tumors,22 suggesting the antibody effect may involve a host-antibody connection not detectable in tumor cell autonomous experiments and/or loss of function of PTEN. D. Signaling through bypass pathways (e.g., emanating from MET, IGF-1R, EphA2, or EpoR) participate the downstream effectors of HER2 such as PI3K-Akt either directly or through intracellular kinases such as Src. II. INTRINSIC HER2 ALTERATIONS A mechanism of resistance to inhibitors of HER2 is definitely mutation of the prospective itself, resulting in alteration of drug binding. This mechanism is exemplified from the acquired so-called gatekeeper kinase website mutations observed in individuals with lung malignancy treated with EGFR TKIs and individuals with CML and gastrointestinal stromal tumors treated with imatinib.27C32 For HER2, this would also include mutations in the juxtamembrane region that contains the binding epitope of trastuzumab. Anido et al. explained p95-HER2, a truncated form of HER2 lacking the antibody binding region, which arises from alternate transcription initiation sites in HER2.33 This form of HER2 retains kinase activity and is susceptible to inhibition by lapatinib but not trastuzumab.34 Individuals with metastatic breast malignancy harboring cytosolic expression of p95-HER2 show a very low response rate to treatment with trastuzumab and chemotherapy compared to those individuals without p95-HER2 in their tumors. Conversely, tumors with p95-HER2 are still susceptible to kinase inhibition having a TKI, as was suggested by a similar response rate to capecitabine and lapatinib observed in individuals with breast malignancy with and without p95-HER2.35 A recent study reported a nuclear localized truncated form of HER2, also 95 kDa in size, which retains phosphorylation and nuclear localization upon treatment with lapatinib.36 The frequency and clinical significance of this finding are unknown at this time. A splice variant that eliminates exon 16 in the extracellular website of the HER2 receptor has also been recognized in HER2+ breast cancers and cell lines.37,38 Cell lines expressing this D16 HER2 isoform are resistant to trastuzumab.38,39 This variant does MLN4924 (Pevonedistat) not eliminate the trastuzumab epitope on HER2, but does appear to stabilize HER2 homodimers and may potentially prevent their disruption upon binding from the antibody.38 In addition, the D16 isoform was found to interact directly with the Src tyrosine kinase, and treatment with the Src inhibitor dasatinib overcame the resistance to trastuzumab conferred by the alternative splicing variant.39 A role for Src kinases in HER2 inhibitor resistance will be further discussed below. Point mutations or small insertions in the HER2 gene have been identified in additional cancers. A small quantity (2%C4%) of non-small-cell lung cancers (NSCLC), as well as gastric, colorectal, and head and neck cancers, have been found to have alterations in the HER2 gene.40C46 These include primarily amino acid substitutions or insertions localized in the kinase website. An insertion in exon 20, originally recognized in NSCLC, was able to confer resistance to lapatinib and trastuzumab when indicated in breast malignancy cell lines.47 HER2 mutations have been reported in a small number of human being breast cancers but in the absence of HER2 gene amplification.41 To our knowledge, HER2 mutations in HER2-overexpressing breast tumors have not been reported to date. One possible reason is that these mutations may comprise only a portion of the amplified HER2 alleles and, consequently, exist below the limits of level of sensitivity of traditional DNA sequencing methods. Nonetheless, using a next-generation sequencing approach with higher level of sensitivity that was measured to detect a variant rate of recurrence as low as 0.08%, no mutations in HER2+ breast cell lines or tumors were recognized.48 Another probability is that these mutations may be selected for or acquired only after the selective pressure of anti-HER2 treatment. If so, they are likely to be recognized in tumors that are progressing after main HER2-targeted therapy. Finally, unique for the case of trastuzumab is the possibility of abrogating drug binding to the prospective by coexpression of another protein that binds to the drug target. For example, mucin-4 (MUC4), a membrane-associated glycoprotein, when overexpressed can co-localize with HER2 and face mask the binding site for trastuzumab.49,50 A cleaved form of another mucin family member, MUC1*,.Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. medical studies. These mechanisms involve alterations to HER2 itself, coexpression or acquisition of bypass signaling through additional receptor or intracellular signaling pathways, problems in mechanisms of cell cycle rules or apoptosis, and sponsor factors that may modulate drug response. Emerging medical evidence already suggests that mixtures of therapies focusing on HER2 as well as these resistance pathways will be effective in overcoming or preventing resistance. than does lapatinib, was shown to induce apoptosis in main HER2+ tumors,22 suggesting the antibody effect may involve a host-antibody connection not detectable in tumor cell autonomous experiments and/or loss of function of PTEN. D. Signaling through bypass pathways (e.g., emanating from MET, IGF-1R, EphA2, or EpoR) participate the downstream effectors of HER2 such as PI3K-Akt either directly or through intracellular kinases such as Src. II. INTRINSIC HER2 ALTERATIONS A mechanism of resistance to inhibitors of HER2 is definitely mutation of the prospective itself, resulting in alteration of drug binding. This mechanism is exemplified from the acquired so-called gatekeeper kinase website mutations observed in individuals with lung malignancy treated with EGFR TKIs and individuals with CML and gastrointestinal stromal tumors treated with imatinib.27C32 For HER2, this would also include mutations in the juxtamembrane region that contains the binding epitope of trastuzumab. Anido et al. described p95-HER2, a truncated form of HER2 lacking the antibody binding region, which arises from alternate transcription initiation sites in HER2.33 This form of HER2 retains kinase activity and is susceptible to inhibition by lapatinib but not trastuzumab.34 Patients with metastatic breast malignancy harboring cytosolic expression of p95-HER2 exhibit a very low response rate to treatment with trastuzumab and chemotherapy compared to those patients without p95-HER2 in their tumors. Conversely, tumors with p95-HER2 are still susceptible to kinase inhibition with a TKI, as was suggested by a similar response rate to capecitabine and lapatinib observed in patients with breast malignancy with and without p95-HER2.35 A recent study reported a nuclear localized truncated form of HER2, also 95 kDa in size, which retains phosphorylation and nuclear localization upon treatment with lapatinib.36 The frequency and clinical significance of this finding are unknown at this time. A splice variant that eliminates exon 16 in the extracellular domain name of the HER2 receptor has also been identified in HER2+ breast cancers and cell lines.37,38 Cell lines expressing this D16 HER2 isoform are resistant to trastuzumab.38,39 This variant does not eliminate the trastuzumab epitope on HER2, but does appear to stabilize HER2 homodimers and may potentially prevent their disruption upon binding by the antibody.38 In addition, the D16 isoform was found to interact directly with the Src tyrosine kinase, and treatment with the Src inhibitor dasatinib overcame the resistance to trastuzumab conferred by the alternative splicing variant.39 A role for Src kinases in HER2 inhibitor resistance will be further discussed below. Point mutations or small insertions in the HER2 gene have been identified in other cancers. A small number (2%C4%) of non-small-cell lung cancers (NSCLC), as well as gastric, colorectal, and head and neck cancers, have been found to have alterations in the HER2 gene.40C46 These include primarily amino acid substitutions or insertions localized in the kinase domain name. An insertion in exon 20, originally identified in NSCLC, was able to confer resistance to lapatinib and trastuzumab when expressed in breast malignancy cell lines.47 HER2 mutations have been reported in a small number of human breast cancers but in the absence of HER2 gene amplification.41 To our knowledge, HER2 mutations in HER2-overexpressing breast tumors have not been reported to date. One possible reason is that these mutations may comprise only a portion of the amplified HER2 alleles and, therefore, exist below the limits of sensitivity of traditional DNA sequencing methods. Nonetheless, using a next-generation sequencing approach with higher sensitivity that was measured Rabbit Polyclonal to CD3EAP to detect a variant frequency as low as 0.08%, no mutations in HER2+ breast cell lines or tumors were detected.48 Another possibility is that these mutations may be selected for or acquired only after the selective pressure of anti-HER2 treatment. If so, they are likely to be detected in tumors that are progressing after primary.
Mix of lapatinib and a SFK inhibitor partially blocked PI3K activation in the resistant cells and restored sensitivity to lapatinib in BT474 xenografts
