Repurposing of bisphosphonates for the prevention and therapy of nonsmall cell lung and breast cancer

A variety of human cancers, including nonsmall cell lung (NSCLC), breast, and colon cancers, are driven by the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases. Having shown that bisphosphonates, a class of drugs used widely for the therapy of osteoporosis and metastatic bone disease, reduce cancer cell viability by targeting HER1, we explored their potential utility in the prevention and therapy of HER-driven cancers. We show that bisphosphonates inhibit colony formation by HER1^ΔE746-A750-driven HCC827 NSCLCs and HER1^wt-expressing MB231 triple negative breast cancers, but not by HER^low-SW620 colon cancers. In parallel, oral gavage with bisphosphonates of mice xenografted with HCC827 or MB231 cells led to a significant reduction in tumor volume in both treatment and prevention protocols. This result was not seen with mice harboring HER^low SW620 xenografts. We next explored whether bisphosphonates can serve as adjunctive therapies to tyrosine kinase inhibitors (TKIs), namely gefitinib and erlotinib, and whether the drugs can target TKI-resistant NSCLCs. In silico docking, together with molecular dynamics and anisotropic network modeling, showed that bisphosphonates bind to TKIs within the HER1 kinase domain. As predicted from this combinatorial binding, bisphosphonates enhanced the effects of TKIs in reducing cell viability and driving tumor regression in mice. Impressively, the drugs also overcame erlotinib resistance acquired through the gatekeeper mutation T790M, thus offering an option for TKI-resistant NSCLCs. We suggest that bisphosphonates can potentially be repurposed for the prevention and adjunctive therapy of HER1-driven cancers.Bisphosphonates are the most commonly used class of therapeutics for osteoporosis and cancer bone disease, with a proven record of efficacy and safety in people (1, 2). There is increasing evidence, however, that bisphosphonates can directly kill cancer cells (3). We recently showed that aminobisphosphonates can inactivate human epidermal growth factor receptor (HER) family of receptor tyrosine kinases (RTKs) (4). We found that the drugs directly bind the HER1/2 kinase domain and, by inhibiting downstream signaling, reduce the cell viability in HER-driven lung, breast, and colon cancers (4). Knocking down the four HER isoforms abrogate bisphosphonate action, proving a selective action through this pathway (4). Indeed, this new action might explain the reduced disseminated tumor cell burden and increased disease- and recurrence-free survival documented in early breast cancer patients (5–8). The process may also explain epidemiologic observations in which patients on oral bisphosphonates for their osteoporosis had a lower incidence of colon and breast cancer (9–11).Lung cancer is responsible for the largest number of deaths worldwide. About 80% of lung cancers are nonsmall cell cancers (NSCLCs), of which ∼30% are driven by two activating mutations in the HER1 kinase domain (HER1^ΔE746-A750 and HER1^L868R) (12). Since their introduction, tyrosine kinase inhibitors (TKIs), most notably erlotinib and gefitinib, have dramatically improved survival of NSCLC patients (13). However, prolonged therapy for over 3 y invariably results in resistance (14). About 50% of the resistance arises from a second site mutation of the gatekeeper residue T790 to a methionine (15, 16). This mutation results in reduced affinity to TKIs, poor drug efficacy, and a rapid downhill clinical course. In addition, HER1/2 gene amplification and overexpression drive a significant number of breast and colon cancers.Here, we report that bisphosphonates attenuate tumor growth in nude mice xenografted with HER1^ΔE746-A750-driven NSCLCs or HER1^wt-expressing MB231 breast cancer cells. Impressively, tumor growth was profoundly reduced with treatment begun at the time of grafting (prevention protocol), whereas mice harboring HER^low-SW620 colon cancers remained resistant. We also provide evidence for combinatorial binding of bisphosphonates and TKIs to the HER1 kinase domain, resulting in additive effects on tumor regression in HER1^ΔE746-A750-grafted mice. We suggest that the two drugs could potentially be used in concert in NSCLC patients. Finally, bisphosphonates retain their ability to inhibit the viability of cells harboring the HER1^T790M gatekeeper mutation, a prelude to their use in overcoming TKI resistance.