Abstract Clinical resistance mechanisms to CDK4/6 inhibitors in HR+ breast cancer have not been clearly defined. Whole exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1 , RAS , AURKA , CCNE2, ERBB2, and FGFR2, and loss of ER expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1 , KRAS , AURKA , or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Besides inactivation of RB1, which accounts for ∼5% of resistance, seven of these mechanisms have not been previously identified as clinical mediators of resistance to CDK4/6 inhibitors in patients. Three of these—RAS activation, AKT activation, and AURKA activation—have not to our knowledge been previously demonstrated preclinically. Together, these eight mechanisms were present in 80% of resistant tumors profiled and may define therapeutic opportunities in patients. Significance We identified eight distinct mechanisms of resistance to CDK4/6 inhibitors present in 80% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR+ MBC.
Abstract Approximately 70% of breast cancers express the estrogen receptor (ER), and estrogen signaling drives breast cancer cell growth and progression. ER-directed therapies are commonly used to treat ER+ breast cancer and have improved survival for patients, yet resistance to those therapies inevitably occurs. Mutations in the estrogen receptor itself occur in ∼25-30% of patients with ER+ metastatic breast cancer that has developed resistance to aromatase inhibitors. Beyond these ER mutations, other resistance mechanisms are not well described. Moreover, clinical mechanisms of resistance to another class of ER-targeted agents, selective estrogen receptor degraders (SERDs), such as fulvestrant have not been clearly identified. Here we report two FGFR2 mutations identified in patients with resistant ER+ metastatic breast cancer, N550K and M538I. N550K is a well-known activating FGFR2 mutation; M538I stabilizes the active kinase conformation and it has not previously been described in breast cancer. When expressed in ER+ T47D cells, FGFR2 M538I and N550K led to resistance to fulvestrant, and the CDK4/6 inhibitor palbociclib and the combination of the two agents. FGFR2 M538I induced hyperactivity of p-FRS2, p-ERK and p-AKT, which is higher than wildtype FGFR2 and comparable to other known activating mutations N550K and K660N. In addition, overexpression of M538I mutant reduced sensitivity to FGFR inhibitors PD173074 and dovitinib in T47D cells, suggesting M538I is also functionally activating. Due to the hyperactive downstream signaling elicited by the mutation, cells overexpressing FGFR2 M538I achieved optimal growth in the presence of low dose of FGFR inhibitor. Under such conditions, FGFR2 M538I conferred more potent resistance to fulvestrant as compared to wildtype FGFR2. However, drug resistance resulting from M538I mutant can be fully resensitized to fulvestrant and/or palbociclib with high dose of FGFR inhibitors. In summary, we have identified activating FGFR2 mutations (M538I and N550K) in ER+ breast cancer patients, which may contribute to the development of resistance to SERDs and CDK4/6 inhibitors. Additional FGFR2 mutations have been recently identified in other cohorts of patients with resistant ER+ metastatic breast cancer, suggesting that this may be a clinical mechanism of resistance in some patients. Patients with activating FGFR2 mutations may benefit from the treatment with an FGFR inhibitor in combination with SERDs and CDK4/6 inhibitors. Citation Format: Mao P, Kusiel J, Cohen O, Wagle N. The role of FGF/FGFR axis in resistance to SERDs and CDK4/6 inhibitors in ER+ breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD4-01.
<div>Abstract<p>Durable control of invasive solid tumors necessitates identifying therapeutic resistance mechanisms and effective drug combinations. In this work, we used a network-based mathematical model to identify sensitivity regulators and drug combinations for the PI3Kα inhibitor alpelisib in estrogen receptor positive (ER<sup>+</sup>) <i>PIK3CA</i>-mutant breast cancer. The model-predicted efficacious combination of alpelisib and BH3 mimetics, for example, MCL1 inhibitors, was experimentally validated in ER<sup>+</sup> breast cancer cell lines. Consistent with the model, FOXO3 downregulation reduced sensitivity to alpelisib, revealing a novel potential resistance mechanism. Cell line–specific sensitivity to combinations of alpelisib and BH3 mimetics depended on which BCL2 family members were highly expressed. On the basis of these results, newly developed cell line–specific network models were able to recapitulate the observed differential response to alpelisib and BH3 mimetics. This approach illustrates how network-based mathematical models can contribute to overcoming the challenge of cancer drug resistance.</p>Significance:<p>Network-based mathematical models of oncogenic signaling and experimental validation of its predictions can identify resistance mechanisms for targeted therapies, as this study demonstrates for PI3Kα-specific inhibitors in breast cancer.</p></div>
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